Cognitive Enhancers (Nootropics). Part 3: Drugs ...€¦ · nootropics, peptides, psychostimulants, stem cells, tau, vaccines INTRODUCTION As of June 14, 2014, there are 28,317 entries

Journal of Alzheimer’s Disease 42 (2014) 1079–1149DOI 10.3233/JAD-141206IOS Press

1079

Review

Cognitive Enhancers (Nootropics). Part 3:Drugs Interacting with Targets other thanReceptors or Enzymes. Disease-ModifyingDrugs. Update 2014

Wolfgang Froestl∗, Andrea Pfeifer and Andreas MuhsAC Immune SA, EPFL, Lausanne, Switzerland

Accepted 12 June 2014

Abstract. Scientists working in the field of Alzheimer’s disease and, in particular, cognitive enhancers, are very productive. Thereview “Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs” was accepted in October2012. In the last 20 months, new targets for the potential treatment of Alzheimer’s disease were identified. Enormous progresswas realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review coversthe evolution of research in this field through May 2014.

Keywords: Amyloid-� aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products,nootropics, peptides, psychostimulants, stem cells, tau, vaccines

INTRODUCTION

As of June 14, 2014, there are 28,317 entries inPubMed under the term cognitive enhancers, 28,336entries under the term nootropic, and 313 entriesunder the term cognition enhancers. Scifinder lists5,732 references under the research topic nootropic,661 references under the term cognitive enhancer, and11,334 references for cognition enhancers. The Thom-son Reuters Cortellis database lists 1,306 drugs asnootropic agents. The term nootropics was coined bythe father of piracetam Corneliu Giurgea in 1972/1973[1, 2] NOOS = mind and TROPEIN = toward.

Nootropics are drugs to treat cognition deficits,which are most commonly found in patients sufferingfrom Alzheimer’s disease (AD), schizophrenia, stroke,attention deficit hyperactivity disorder (ADHD), or

∗Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,EPFL, Innovation Park, Building B, CH-1015 Lausanne, Switzer-land. Tel.: +41 21 693 91 43; Fax: +41 21 693 91 20; E-mail:[email protected].

aging. Mark J. Millan and 24 eminent researchers[3] presented an excellent overview on cognitivedysfunction in psychiatric disorders in the Febru-ary 2012 issue of Nature Reviews Drug Discoveryand define cognition as “a suite of interrelatedconscious (and unconscious) mental activities, includ-ing pre-attentional sensory gating, attention, learningand memory, problem solving, planning, reasoningand judgment, understanding, knowing and repre-senting, creativity, intuition and insight, spontaneousthought, introspection, as well as mental time travel,self-awareness and meta cognition (thinking andknowledge about cognition)”.

Since a first review in 1989 on “Families of Cogni-tion Enhancers” by Froestl and Maıtre [4], substantialprogress has been made in the understanding ofthe mechanism(s) of cognitive enhancers. Therefore,we propose a new classification to assign cognitionenhancing drugs to 19 categories:

1. Drugs interacting with Receptors (Part 1)2. Drugs interacting with Enzymes (Part 2)

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1080 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets

3. Drugs interacting with Cytokines (Part 3)4. Drugs interacting with Gene Expression (Part

3)5. Drugs interacting with Heat Shock Proteins

(Part 3)6. Drugs interacting with Hormones (Part 3)7. Drugs interacting with Ion Channels (non-

Receptors) (Part 3)8. Drugs interacting with Nerve Growth Factors

(Part 3)9. Drugs interacting with Re-uptake Transporters

(Part 3)10. Drugs interacting with Transcription Factors

(Part 3)11. Antioxidants (Part 3)12. Metal Chelators (Part 3)13. Natural Products (Part 3)14. Nootropics (“Drugs without mechanism”)

(Part 3)15. Peptides (Part 3)16. Drugs preventing amyloid-� aggregation (Part

3)16.1. Ligands interacting with amyloid-� (Part 3)16.2. Inhibitors of serum amyloid P component

binding (Part 3)16.3. Vaccines against amyloid-� (Part 3)16.4. Antibodies against amyloid-� (Part 3)

17. Drugs interacting with tau, prion, �-synuclein,ApoE, and TDP-43 (Part 3)

17.1. Drugs preventing tau, prion, or �-synucleinaggregation (Part 3)

17.2. Ligands interacting with tau and �-synuclein(Part 3)

17.3. Vaccines against tau and �-synuclein (Part 3)17.4. Antibodies against tau, superoxide dismutase

1, �-synuclein, and ApoE18. Stem Cells (Part 3)19. Miscellaneous (Part 3)

In the first paper, drugs interacting with receptorswere described [5]; in the second paper, drugs inter-acting with enzymes [6]. In this third part, we give anoverview of drugs interacting with targets 3 to 10 andcompounds and preparations of categories 11 to 19 [7].Disease modifying drugs are aimed to counteract theprogression of a disease [8]. �-secretase activators and�- and �-secretase inhibitors (and modulators) werepresented in Part 2 of this series of reviews. Drugsinteracting with amyloid-� (A�) and tau includingimmunotherapy are described in Part 3. For excel-lent novel overviews on therapeutics for AD, see[9–14].

However, this field is very dynamic. Potential newtargets were identified for the treatment of cognitivedeficits. Some compounds progressed in their devel-opment, while many others were discontinued. Thethorough pharmacological characterization of natu-ral products with cognitive enhancing properties wassignificantly expanded. Therefore, an update is appro-priate.

DRUGS INTERACTING WITH CYTOKINES

There is abundant evidence that inflammatory mech-anisms within the central nervous system (CNS)contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells[15]. A current hypothesis is that an extracellular insultto neurons could trigger the production of inflam-matory cytokines by astrocytes and microglia [16].Knocking down the IL-12/23 signaling subunit p40in the brain of SAMP8 mice ameliorated their spa-tial memory [17]. See also Chapter 11. Antioxidants,because inflammation is tightly connected with theoxidative cascade.

Diammonium glycyrrhizinate attenuated A�1-42-induced neuroinflammation and regulated MAPK andNF-κB pathways in vitro and in vivo [18].

The development of SEN-1176 (Senexis; [19]),TT-301 (MW01-6-189WH; MW-189), and TT-302(MW01-7-084WH, MW-084; Transition Therapeu-tics) was terminated.

DRUGS INTERACTING WITH GENEEXPRESSION

A genome-wide association study (GWAS) ofthe rate of cognitive decline in AD revealed thatthe minor alleles of the spondin 1 gene (SPON1)were significantly associated with a slower rate ofcognitive decline [20]. A GWAS implicated theAPOE locus in nonpathological cognitive aging [21].Another GWAS elucidated the correlation betweenbutyrylcholinesterase expression and A� deposits[22].

Apabetalone (RVX-208, Resverlogix, Calgary;Fig. 1) is an apolipoprotein A1 (ApoA1) gene expres-sion stimulator for the potential prevention of A�plaque accumulation in AD. In January 2011, data froman analysis of AD biomarkers in the Phase II ASSERTtrial in 299 patients showed that after 12 weeks oftreatment with 150 mg/day, a positive effect on A�40was seen. Apabetalone significantly increased HDL-

W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets 1081

Fig. 1. A drug interacting with gene expression, a heat shock protein inhibitor, a GIRK activator, and a p75 neurotrophin receptor ligand.

C (p = 0.001), the primary endpoint of the Phase IIbSUSTAIN trial. SUSTAIN also successfully met sec-ondary endpoints and showed increases in levels ofApo-AI (p = 0.002) and large HDL particles (p = 0.02),both believed to be important factors in enhancingreverse cholesterol transport activity. Apabetalone isa unique selective bromo and extraterminal (BET)bromodomain antagonist [23, 24] (Thomson ReutersPharma, update of June 12, 2014).

There are several drugs interacting with gene expres-sion in preclinical evaluation (in alphabetical order):

Adeno-associated virus vector-5-deliveredGDNF gene therapy (Cedars-Sinai RegenerativeMedicine Institute, Los Angeles, CA) secreted glialcell-derived neurotrophic factor (GDNF) directly intomuscle cells for the potential treatment of amyotrophiclateral sclerosis (ALS) (Thomson Reuters Pharma,update of April 4, 2014).

Crct-1 gene therapy (Universitat Autonoma deBarcelona) acts by inducing the production of CREBregulated transcription coactivator-1 (Crtc1) for thepotential prevention and treatment of AD. The genetherapy activated Crtc1 and prevented the loss of mem-

ory in mice (Thomson Reuters Pharma, update of April25, 2014).

DRUGS INTERACTING WITH HEATSHOCK PROTEINS

Overexpression of Hsp27 ameliorated symptoms ofAD in A�PP/PS1 mice [25]. Intranasally-administeredHsp70 rapidly entered the brain and mitigated multipleAD-like morphological and cognitive abnormalities inmodel animals [26]. Tau triage decisions are medi-ated by the chaperone network [27]. Hsp90 inhibits�-synuclein aggregation by interacting with solubleoligomers [28].

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of Hsp90. A highdose of 17-AAG decreased neurofibrillary tangles inmale P301L mutant mice [29]. It attenuated A�-induced synaptic toxicity and memory impairment[30].

University of Siena medicinal chemists publishednovel 1,2,3-triazoles as Hsp90 inhibitors [31].


YM-08 (University of Michigan, Ann Arbor, MI;Fig. 1) is a novel brain penetrant Hsp70 inhibitor,which reduced phosphorylated tau levels in culturedbrain slices [32]. The allosteric heat shock protein 70inhibitor YM-01 (University of South Florida, Tampa,FL) rapidly rescued synaptic plasticity deficits byreducing aberrant tau [33].

A new class of Hsp90 inhibitors designed by energy-based pharmacophore virtual screening was described[34].

An excellent review on heat shock proteins was pub-lished recently [35].

The development of Hsp90 inhibitors of Lundbeckwas terminated.

DRUGS INTERACTING WITH HORMONES

Melanocortins, in particular MC4 receptor-stimulation melanocortins, protected againstprogression of AD in triple transgenic mice [36].

Resistin, also known as adipose tissue-specificsecretory factor or C/EBP-�-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is acysteine-rich adipose-derived peptide hormone, pro-tected against endogenous A� neuronal cytotoxicity[37].

The development of leuprolide acetate implant(VP-4896, Memryte; Curaxis Pharmaceuticals andDURECT) was terminated.

DRUGS INTERACTING WITH IONCHANNELS (NON-RECEPTORS)

Dysregulation of Ca2+ homeostasis plays a crucialrole in the pathogenesis of AD [38–42]. The topic “Cal-cium channel blockers and dementia” was discussed[43].

ARC-029 (Archer Pharmaceuticals, Sarasota, FL,a spin-out from the Roskamp Institute, Sarasota, FL)is a blood-brain barrier crossing formulation of nil-vadipine (for the structure, see [7]). It is evaluated ina multisite Phase III clinical trial enrolling more than500 AD patients in Europe since May 2013 (ThomsonReuters Pharma, update of May 20, 2013).

RNS-60 (Revalesio Corporation, Tacoma, WA) isin Phase II clinical trials since May 2010. RNS-60enhanced synaptic transmission and induced mor-phological plasticity by stimulating NMDA- andAMPA-dependent calcium influx [44] (ThomsonReuters Pharma, update of May 16, 2014). The struc-ture was not communicated.

ST-101 (ZSET-1446; Sonexa Therapeutics, SanDiego, CA under license from Zenyaku Kogyo, Tokyo)is in Phase II clinical trials for AD since Febru-ary 2009 and for the treatment of essential tremorsince May 2011 (for the structure, see [7]). Combi-nation effects of ZSET1446/ST101 with memantineon cognitive function and extracellular acetylcholinein the hippocampus of rats were described [45]. It wasrecognized that ST-101 targeted T-type voltage-gatedcalcium channels in mediating improved cognition inthe CNS [46] (Thomson Reuters Pharma, update ofOctober 8, 2013).

Phenchlobenpyrrone (Yunnan Spirin Biotechnol-ogy, Kunming Yunnan, the Kunming Institute ofBotany of the Chinese Academy of Sciences and theKunming Institute of Zoology of the Chinese Academyof Sciences, Kunming Yunnan, China) is a nerve cellcalcium channel blocker and glycine receptor antag-onist for the potential treatment of AD and amnesiain Phase I clinical trials since May 2008 (ThomsonReuters Pharma, update of October 4, 2013). The struc-ture was not communicated.

ML-297 (VU-0456810; CID-56642816; VanderbiltUniversity, Nashville, TN and AfaSci, Burlingame,CA; Fig. 1) is a selective G-protein coupled inwardrectifying potassium (GIRK) channel activator for thepotential treatment of epilepsy. ML-297 improved cog-nitive activity in mice (Thomson Reuters Pharma,update of June 30, 2014).

Tx3-1, a peptidic toxin and selective blocker ofA-type K+ currents (IA), enhanced both short- andlong-term memory consolidation of mice tested inthe novel object recognition task. Moreover, Tx3-1restored memory of A�25-35-injected mice [47].

Topiramate (Johnson & Johnson, launched in 1996)is a blocker of voltage-dependent sodium channelsand widely used as an antiepileptic drug. It allevi-ated behavioral deficits and reduced neuropathologyin A�PPSWE/PS1dE9 transgenic mice [48]. It wastested in clinical settings for the treatment of aggressivebehavior in dementia [49–51].

The development of ARC-031-SR (a non-calciumchannel blocking and soluble A� reducing nilvadip-ine derivative in a slow release formulation, ArcherPharmaceuticals) and of SPI-017 oral (Sucampo) wasterminated.

DRUGS INTERACTING WITH NERVEGROWTH FACTORS

Early brain-derived neurotrophic factor (BDNF)treatment ameliorated cell loss in the entorhinal cortex


of A�PP transgenic mice [52]. A� oligomers impairedBDNF retrograde trafficking by down regulating ubiq-uitin C-terminal hydrolase, UCH-L1 [53]. PlasmaBDNF levels are correlated with aggressiveness inpatients with amnestic mild cognitive impairment(aMCI) or AD [54]. Decreased levels of BDNF werefound in patients with non-AD tauopathies [55].

Nerve growth factor (NGF) and AD, new factsfor an old hypotheses were communicated [56, 57].Nerve growth factor metabolic dysfunction in ADand Down’s syndrome was reviewed recently [868].Ganglioside GM1 treatment prevented A�-inducedcognitive deficits in rats by preventing A�-inducedalteration on Na+, K+-ATPase by its antioxidant prop-erties [58].

NeuroAid (MLC-601; Danqi Plantan Jiaonang;Moleac Pte Ltd, Singapore) is a BDNF stimulator forthe potential oral prevention of stroke including cere-bral infarction and ischemic stroke and for the potentialtreatment of traumatic brain injury (TBI) in a random-ized, double-blind, placebo-controlled, multicenter,Phase III trial (n = 1100) since November 2007 in Sin-gapore and the Philippines. The drug was launched inSingapore in February 2013 for the treatment of cere-bral infarction and ischemic stroke (Thomson ReutersPharma, update of April 28, 2014).

NeuroAiD II (MLC-901, Moleac Pte Ltd., Singa-pore), a BDNF stimulator, is a derivative of NeuroAiDfor the potential treatment of global ischemia. Itwas launched in Europe in February 2013 (ThomsonReuters Pharma, update of September 27, 2013).

CERE-110 (AAV2-NGF, NeuroRescue AD; Sang-amo BioSciences, Richmond, CA, following theacquisition of Ceregene, San Diego, CA) is an AAV2vector based gene delivery system containing cDNAfor NGF in Phase II clinical trials in mild-to-moderateAD patients (n = 50) since May 2009 in the US. InApril 2013, top-line data were expected by late 2014(Thomson Reuters Pharma, update of June 2, 2014).

GM-609 (Genervon Biopharmaceuticals, Pasadena,CA) is a motoneuronotrophic factor analogue of thestructure H2N-Phe-Ser-Arg-Tyr-Ala-Arg-COOH forthe potential treatment of ischemic stroke, spinal cordinjuries, ALS, AD, Huntington’s disease (HD), andParkinson’s disease (PD). By April 2011 a Phase IIischemic stroke trial was initiated. By December 2012,a Phase II clinical trial was initiated for PD (ThomsonReuters Pharma, update of April 28, 2014).

T-817MA (Toyama Chemical, Tokyo, a whollyowned subsidiary of Fujifilm Holding, Tokyo) is a neu-rotrophic small molecule in Phase II clinical trials forAD in the US since April 2008. For the structure, see

[7] (Thomson Reuters Pharma, update of May 6, 2014).There are several drugs or preparations interacting

with neurotrophic factors in preclinical evaluation (inalphabetical order):

299-B-5 (Molcode, Tartu, Estonia) is a smallmolecule mimetic of GDNF, which activated theGDNF family receptor-�/RET receptor complex forthe potential treatment of neurological disease includ-ing ALS, neuropathic pain, PD, and AD (ThomsonReuters Pharma, update of September 27, 2013). Thestructure was not communicated.

AM-206 (Seoul National University) is anantagomir, which enhanced BDNF levels, synap-togenesis, and neurogenesis including cognitiveimprovement in an AD transgenic mouse model. ByJanuary 2013, studies had shown that the lead com-pound was effectively delivered to the brain throughintranasal delivery by crossing the blood-brain barrier.Data also showed that the cognitive function wasrestored through synapse regeneration in mice withAD (Thomson Reuters Pharma, update of July 12,2013).

Basic fibroblast growth factor entrapped innanoparticles (Fudan University, Shanghai) signifi-cantly improved spatial learning and memory in ADrats following intranasal administration [59].

KP-546 (CeneRx Biopharma, Cary NC underlicense from Krenitsky Pharmaceuticals, Durham,NC) is an orally active small molecule NGF stim-ulator for the potential prevention and treatment ofchemotherapy-induced neuropathy and neurodegen-erative disorders including AD (Thomson ReutersPharma, update of April 2, 2013). The structure wasnot communicated.

LM11A-31-BHS (PharmatrophiX, Raleigh, NC,Fig. 1) is a p75 neurotrophin receptor ligand for thepotential oral treatment of AD [60]. It reduced patho-logical phosphorylation and misfolding of tau [61](Thomson Reuters Pharma, update of April 4, 2014).

Neuropep-1, a BDNF modulating peptide, amelio-rated learning and memory deficits in an AD mousemodel [62].

PRCN-226 (Neuralgene, Colombia, USA in con-junction with Precision StemCell of Bogota, Colom-bia) is a neurotropic adeno-associated virus (AAV)vector gene therapy that enhances dopaminergic neu-rons for the potential treatment of PD (ThomsonReuters Pharma, update of May 1, 2013).

The development of drugs interacting with neu-rotrophic factors (in alphabetical order) was ter-minated: of AL-209 (ADNF-9, SAL) and AL-309(Allon Therapeutics), CB-1, CB-2, and CB-3 (BDNF


Fig. 2. An EAAT stimulator, a choline transporter inhibitor, and a VMAT2 PET ligand.

mimetics; Molcode), KP-544 (KRX-0501, CXB-909;Krenitsky), leteprinim (AIT-082; SPI-205, Neotrofin;Spectrum Pharmaceuticals, Henderson, NV formerlyNeoTherapeutics). It is now evaluated in a Phase I clin-ical trial for the potential treatment of chemotherapy-induced neuropathy since December 2012 in theUS; Thomson Reuters Pharma, update of March 25,2014), NGF agonists (Rhone-Poulenc/Regeneron),Pan-Neurotrophin-1 (Regeneron) and PYM-50028(Smilagenin, Cogane, P58, P63; Phytopharm; [63]).

DRUGS INTERACTING WITH RE-UPTAKETRANSPORTERS (PSYCHOSTIMULANTS)

For a recent review on psychostimulants and cogni-tion, see [64]. An analysis of student use (and abuse)of cognitive enhancers was presented [65].

There are several drugs interacting with re-uptaketransporters in preclinical evaluation (in alphabeticalorder):

AMY-GLY-1, AMY-GLY-3, and AMY-GLY6(Albany Molecular Research, Albany, NY) are glycinetransporter-1 (GlyT-1) inhibitors for the potential treat-ment of schizophrenia (Thomson Reuters Pharma,update of September 26, 2013). The structures werenot communicated.

Excitatory amino acid transporter-2 (EAAT-2)stimulators (Fig. 2) are investigated by scientists fromthe Ohio State University (Columbus, OH) in collabo-ration with the Brigham & Women’s Hospital (Boston,MA) for the potential treatment of neurodegenerativediseases (Thomson Reuters Pharma, update of July 23,2013).

Glycine transporter-1 (GlyT-1) inhibitors areevaluated for the potential treatment of cognitiveimpairments in patients with AD and schizophreniaby the company Dart NeuroScience LLC (San Diego,CA) (Thomson Reuters Pharma, update of January 30,2013). Structures were not communicated.

ML-352 (Vanderbilt University, Nashville, TN;Fig. 2) is a novel choline transporter inhibitor for thepotential treatment of AD (Thomson Reuters Pharma,update of September 18, 2013).

Selective Serotonin Re-uptake Inhibitors (SSRIs)showed cognitive enhancing effects [869]. Patientstreated with citalopram showed significant improve-ments on a cognitive subscale. Citalopram dose-dependently decreased amyloid-� in brain interstitialfluid. It arrested the growth of preexisting plaques andreduced the appearance of new plaques by 78%. Theability to safely decrease A� concentration is poten-tially important as a preventive strategy for AD [870].

The development of AHN 2-005 (National Insti-tute of Drug Abuse and US Naval Medical ResearchCenter), of AMG-747 (a GlyT-1 inhibitor; Amgen),ASP-2535 and AS-1522489-00 (GlyT-1 inhibitors;Astellas; [66]), bitopertin (RG-1678, Ro-4917838;a GlyT-1 inhibitor, Roche), of flufenoxina (FAESFarma, the preclinical evaluation for the treatment ofdepression is continuing; Thomson Reuters Pharma,update of September 27, 2013), Lu-AA42202 (Lund-beck, a triple dopamine, noradrenaline and serotoninre-uptake inhibitor), and NS-2359 (NeuroSearch) wasterminated.

The vesicular monoamine transporter 2(VMAT2) located on the membrane of vesiclesis responsible for storing and packaging neuro-transmitters into monoamine vesicles or granules.Imaging VMAT2 in the brain provides a measurementreflecting the integrity of dopaminergic, noradrenergicand serotonergic neurons [67]. Positron emissiontomography (PET) ligands for the VMAT2 becamevaluable diagnostic tools.

18F-Florbenazine (18F-AV-133; 18F-FP-DTBZ;Avid Radiopharmaceuticals, Philadelphia PA, a sub-sidiary of Eli Lilly, Indianapolis, IN under license fromthe University of Michigan, Ann Arbor, MI; Fig. 2) isin Phase III clinical evaluation. In May 2012, an open-


label, single-blind, Phase II/III study (NCT01550484;18F-AV-133-B04) was initiated in patients with undiag-nosed movement disorders (n = 150) in the US to assessthe safety and efficacy of florbenazine in diagnosingPD. At that time the study was scheduled to completein September 2014. Preclinical and clinical data werepublished [68, 69] (Thomson Reuters Pharma, updateof April 25, 2014).

DRUGS INTERACTING WITHTRANSCRIPTION FACTORS

No new developments.

ANTIOXIDANTS

Oxidative stress in AD was reviewed [70]. Oxida-tive stress mediated mitochondrial and vascular lesionsserve as markers in the pathogenesis of AD [71]. Seealso Chapter 3: Cytokines, as inflammation is tightlyconnected with the oxidative cascade.

Over years clinicians have explored treatment ofAD patients with antioxidants. Free radicals can bescavenged by dietary means. For a review on diet,cognition, and AD, see [72]. In the TEAM-AD VAcooperative randomized trial, patients with mild tomoderate AD receiving �-tocopherol showed a slowerfunctional decline compared with placebo [73]. Par-

ticipants received either 2,000 IU/d �-tocopherol,memantine, the combination, or placebo. There wereno significant differences in the groups receivingmemantine alone or memantine plus �-tocopherol. Fora comment, see [74]. The combination of omega-3 fattyacid and �-lipoic acid slowed cognitive and functionaldecline in AD patients over 12 months [75].

BN-82541 (Ipsen, Boulogne-Billancourt, France,Fig. 3) is a mitochondrial protectant with antioxidant,COX-1/2 inhibitory and selective Na+ channel block-ing activities for the potential treatment of HD andPD. In January 2014, the drug was listed as beingin Phase II development for HD (Thomson ReutersPharma, update of January 7, 2014).

VP-20629 (OX1; IN-OX1; OX1; OXIGON, Indole-3-propionic acid; ViroPharma, Exton PA, under licensefrom Intellect Neurosciences, New York Universityand Mindset BioPharmaceuticals) is an antioxidant andA� aggregation/deposition inhibitor for the treatmentof Friedreich’s ataxia. A Phase II clinical trial wasinitiated in January 2014 (Thomson Reuters Pharma,update of March 13, 2014).

There are several antioxidants in preclinical evalua-tion (in alphabetical order):

CAT-SKL is a cell-penetrating, peroxisome-targeted, protein biologic, which entered neurons andreversed A�-induced oxidative stress [76].

CNSB-002 (AM-36; Relevare, Melbourne; for-merly Zenyth Therapeutics; Fig. 3) is an antioxidant,

Fig. 3. Antioxidants.


sodium channel blocker and sigma opioid modulatorfor the potential treatment of inflammatory and neuro-pathic pain [77–79] (Thomson Reuters Pharma, updateof July 21, 2014).

JHX-4 (University of Nebraska Medical Center(UNMC), Omaha, NE; Fig. 3) has antioxidant andmetal chelating activity for the potential oral treatmentof age-related diseases such as macular degeneration,cataract and AD (Thomson Reuters Pharma, update ofApril 3, 2013).

L-NNNBP (Fourth Military Medical University,Xi’an, China) is a new chiral pyrrolyl-�-nitronylnitroxide radical showing potential antioxidant effects.It inhibited cell apoptosis induced by A� exposure. Invivo treatment for 1 month induced a marked decreasein brain A� deposition and tau phosphorylation inA�PP/PS1 transgenic mice [80].

Nicotinamide forestalled pathology and cognitivedecline in AD mice [81]. It also reduced the levels ofoxidative stress, apoptosis, and PARP-1 activity in anA�1-42-induced rat model of AD [82].

Nicotinamide riboside restored cognition in ADmouse models [83].

Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) improved memory deficits and attenuated A�and tau pathologies in a mouse model of AD [84]Its neuroprotective effects are probably due to anattenuation of hydrogen peroxide-induced apoptosis[85].

SkQ1 (plastoquinonyl-decyltriphenylphosphoniumbromide, Fig. 3) is a mitochondria-targeted antioxi-dant, which partially retarded AD-like pathology insenescence-accelerated OXYS rats [86, 87].

The development of antioxidants was termi-nated: of disufenton sodium (Cerovive, NXY-059,AstraZeneca, which was in Phase III clinical trials forthe treatment of acute ischemic stroke; [88]; the com-pany Onconos, Oklahoma City, OK investigates thedrug for the potential treatment of cancer includingmalignant glioma; Thomson Reuters Pharma, updateof April 17, 2014) and of FRP-0924 (gemifloxacin,Neuron BioPharma).

METAL CHELATORS

The metallobiology of AD was investigated in greatdetail. Excellent reviews were published (in chronolog-ical order) 2012: [89], 2013: [90–93], 2014: [94–97].The current understanding of the roles of A�, tau,and metal ions in AD pathogenesis was describedrecently [98]. For reviews on selenium and AD, see[99, 100]. High manganese induced amyloid-�

related cognitive impairment [871]. For age-associatedchanges of brain copper, iron, and zinc in AD see [872].

DP-b99 (D-Pharm, Rehovot, Israel) is an i.v. pro-drug of the calcium and zinc chelator BAPTA for thepotential treatment of stroke and TBI in Phase III clin-ical trials for stroke since October 2009 in the US,Canada, Europe, Israel, South Africa, and Brazil andsince August 20011 in South Korea. For the structure,see [7]. (Thomson Reuters Pharma, update of June 13,2014).

Several metal chelators are currently in preclinicalevaluation (in alphabetical order):

p,p’-Methoxy-diphenyl diselenide (University ofSanta Maria, Rio Grande do Sul, Brazil and Univer-sity of Lisbon) showed neuroprotective effects in amodel of sporadic dementia of Alzheimer-type in mice[101–104].

NA-571 (Nerve Access, Chicago Ridge, IL) isa nasal formulation of clioquinol for the potentialtreatment of neurodegenerative diseases. Clioquinol,however, caused subacute myelo-optico-neuropathy[105] (Thomson Reuters Pharma, update of April 3,2014).

PBT-434 (Prana Biotechnology, Melbourne, AUS)is an orally active copper/zinc ligand and �-synucleinand protein DJ-1 (PARK7) modulator for the poten-tial treatment of PD [873] (Thomson Reuters Pharma,update of September 4, 2013). The structure was notcommunicated.

2-Phenylethynyl-butyltellurium attenuatedA�25-35-induced learning and memory impairmentsin mice [106].

Selenomethionine, a major organic form of sele-nium in yeasts, plants, and mammals, amelioratedcognitive decline, reduced tau hyperphosphorylationand reversed synaptic deficit in triple transgenic ADmice [107].

A Tetrachloro-Platinum complex on a 8-(1H-benzoimidazol-2-yl)-quinoline (8-BQ) scaffold wasshown to reduce the number of A� plaques by 29%after an oral treatment for 18 weeks of Tg2576 micewith a daily dose of 15 mg/kg [108].

Triazole-pyridine derivatives as inhibitors ofmetal-induced A� aggregation were described [109].

Triethylene tetramine dihydrochloride (trien-tine), a Cu2+-selective chelator, reduced BACE1 activ-ity and mitigated amyloidosis via the AGE/RAGE/NF-κB pathway in a transgenic mouse model of AD[110].

The development of AEN-100 (Synthetic Biolog-ics, formerly Adeona Pharmaceuticals) and Aom-0937(Hangzhou Adamerck Pharmlabs) was terminated.


Fig. 4. Natural products.

NATURAL PRODUCTS

Excellent reviews on naturally occurring phyto-chemicals for the prevention and treatment of ADand PD were presented [111, 112]. Overviews on“natural substances and AD: from preclinical stud-ies to evidence based medicine” were published [113,114]. The treatment of AD using Chinese medicinalplants was reviewed [115]. For the role of traditionalChinese medicine for neural regeneration, see [116].Marine natural products showed acetylcholinesteraseinhibiting properties [117]. Screening and identifica-tion of neuroprotective compounds relevant for ADfrom medicinal plants of Sao Tome e Principe wasdescribed [874].

(-)-Clausenamide (Beijing Qilin TianshengMedicine under license from the Institute of MateriaMedica Chinese Academy of Sciences, Fig. 4) wasisolated from Clausenia lansium (lour) shells for thepotential treatment of AD [118–120]. By December2012 a Phase II trial had been initiated in AD patientsin China (Thomson Reuters Pharma, update of March1, 2013).

Sodium oligomannurarate (HSH-971; ShanghaiGreen Valley Pharmaceutical under license from theOcean University of China, Shandong), is a marine sul-fated oligosaccharide for the potential treatment of AD[121]. It is in a Phase II clinical study in 252 patientswith mild to moderate AD in China since October 2011(Thomson Reuters Pharma, update of April 19, 2014).The structure was not communicated.

STA-1 (Sinphar Pharmaceutical, DongshanYilan, Taiwan) is an oral capsule formulation ofphenylethanoid glycosides extracted from plants forthe potential treatment of dementia and AD. In March

2002, the drug was in Phase II trials for dementia inChina and in March 2012 in Phase II trials for AD inTaiwan. In 2012 the drug was approved for Phase IItrials in the US (Thomson Reuters Pharma, update ofMarch 14, 2014). The structure was not communicated.

Pinocembrin (DL-0108; CSPC Zhongqi Phar-maceutical Technology, Shijiazhuang, Hebei, underlicense from the Institute of Materia Medica ChineseAcademy of Sciences, Beijing; Fig. 4) is a naturalflavone for the potential i.v. treatment of acute ischemicstroke and for oral treatment of patients with AD. ByDecember 2012 a Phase I trial for acute ischemic strokehad been completed. Several preclinical data werereported [122–124, 125] (Thomson Reuters Pharma,update of March 28, 2014).

There are many natural products in preclinical eval-uation as potential drugs for the treatment of AD (inalphabetical order):

9714 (Jiangzhong Pharmaceutical, Nanchang,China, in collaboration with the Chinese Academy ofMedical Military Services, Beijing) is a compoundextracted from a natural product for the potentialoral treatment of AD (Thomson Reuters Pharma,update of January 31, 2013). The structure was notcommunicated.

6-Shogaol, an active constituent of ginger, atten-uated neuroinflammation and cognitive deficits inanimal models of dementia [126].

Acanthopanax senticosus harms (EAS) extractshowed neuroprotective effects in SH-SY5Y cellsoverexpressing wild-type or A53T mutant �-synuclein[127].

Acetylcorynoline, the major alkaloid componentderived from Corydalis bungeana, a traditionalChinese medical herb, attenuated dopaminergic


neurodegeneration and �-synuclein aggregation in ani-mal models of PD [875, 876].

Acteoside isolated from Orobache minor inhibitedA� aggregation [128].

AF-243 (Dendrogenin B, DDB; 5�-hydroxy-6�-[3-(4-aminobutylamino) propylamino]-cholest-7-en-3�-ol; Affichem, Toulouse, France) is an inducer ofneuron survival and neuronal differentiation for thepotential treatment of PD and AD (Thomson ReutersPharma, update of June 9, 2013).

Agmatine improved cognitive dysfunction in astreptozotocin-induced AD rat model [129]. For therole of agmatine in neurodegenerative disease, see[130].

Akebia saponin D, extracted from a traditionalherbal medicine Dipsacus asper Wall, showed pro-tective effects against ibotenoic acid- and A�-inducedcognitive deficits in rats [131, 132].

Therapeutic albumin (Albutein 20%, Grifols,Barcelona) inhibited A� self-association by selectivelybinding A� aggregates rather than monomers andby preventing further growth of the A� assemblies[133].

Allantoin from Nelumbo nucifera (lotus) on sub-chronic administration of 1, 3 or 10 mg/kg for 7 dayssignificantly increased the latency time measured dur-ing the passive avoidance task in scopolamine-inducedcholinergic blockade and normal naıve mice [134].

Aloe polymannose multinutrient complex elicitedsignificant improvements of the Alzheimer’s DiseaseAssessment Scale - Cognitive Subscale score in ADpatients after 9 and 12 months [135].

Anatabine reduced A� production in vitro and invivo [136, 137].

Annonacin, a chemical found in some fruits suchas the custard apple, increased phosphorylation of tauin the brain of FTDP-17 transgenic mice [138].

Apigenin (4’,5,7-trihydroxyflavone), baicalein, andnordihydroguaiaretic acid were potent inhibitors ofliposome permeabilization by A�42 oligomers [139,140]. The effects of C-glycosylation on the anti-ADpotential of apigenin were described [141]. Apigeninreduced human insulin fibrillation [142].

Arctigenin from Arctium lappa (L.) inhibited A�production by suppressing BACE1 expression and pro-moted A� clearance by enhancing autophagy throughAKT/mTOR signaling inhibition [143, 144].

i.v. Ascorbate (vitamin C) improved spatial mem-ory in middle-aged A�PP/PSEN 1 and wild type mice[145].

Asperthecin, Asperbenzaldehyde, and 2,ω-dihdroxyemodin, secondary metabolites of the

fungus Aspergillus nidulans, inhibited tau aggregation[146].

Astaxanthine (NeuroBio Pharm, Laval, Quebec),a terpene combined with long-chain omega-3 phos-pholipids carrying eicosapentaenoic acid and docosa-hexaenoic acid (DHA) is investigated for neurologicalapplications including AD (Thomson Reuters Pharma,update of May 21, 2014).

Astragaloside IV showed protective effects againstA�1-42 neurotoxicity [147].

Bacopa monnieri (Brahmi) showed memory freerecall enhancing effects in adult humans [148]. Neuro-protective effects in experimental models of dementiawere described [149]. A review on the nootropic herbjust appeared [150]. Doses of 320 mg and 640 mgwere evaluated in a double-blind, placebo-controlledcrossover study in Melbourne [151]. Brahmi may be anovel therapeutic agent for the treatment of cognitivedeficits in schizophrenia [152, 153]. A meta-analysisof randomized controlled clinical trials on cognitiveeffects of Bacopa monnieri extract was published[154]. Improved neuroprotective effects were achievedby combining Bacopa monnieri and Rosmarinus offic-inalis extracts [155].

Baicalein (5,6,7-trihydroxyflavone) protected cor-tical neurons from A�25-35-induced toxicity [156]and in a one dose pre-treatment at 5 and 10 mg/kgi.p. attenuated A�25-35-induced amnesia in mice ina step-through passive avoidance paradigm. Apigenin(4’,5,7-trihydroxyflavone), baicalein and nordihy-droguaiaretic acid were potent inhibitors of liposomepermeabilization by A�42 oligomers [139].

Baicalin, the glucuronide of baicalein, inhibitedthe A�-induced microglial cell activation by via theJAK2/STAT3 signaling pathway [157].

Bajijiasu, a dimeric fructose isolated from the Chi-nese herb Radix Morinda officinalis, protected againstA�-induced neurotoxicity in PC12 cells [158, 159].

Bavachinin and isobavachalcone from Psoraleaefructus modulate the A�42 aggregation processthrough different mechanisms in vitro [160].

Berberine is a primary component of extracts ofCoptidis rhizome and was used in traditional Chinesemedicine for centuries. It attenuated tau hyperphospho-rylation in HEK293 cells [161] and ameliorated A�pathology and cognitive impairment in an AD trans-genic mouse model [162]. It protected n2a cells againstcalyculin induced axonal transport impairment [163].

Betaine attenuated AD-like pathological changesand memory deficits induced by homocysteine [164].Betaine suppressed A� generation by altering A�PPprocessing [165].


Black tea extract and rosmarinic acid werethe most potent mito-protectants of six polyphenolsagainst the toxic effects of A� aggregates [166].

Blueberry (Vaccinium virgatum) leaf extracts pro-tected against A�-induced cytotoxicity and cognitiveimpairment [167].

Bombycis excrementum reduced amyloid-�oligomer-induced memory impairments, neu-rodegeneration and neuroinflammation in mice[877].

DL-3-n-Butylphtalide (CSPC-NBP Pharmaceu-ticals, Shijiazhuang, Hebei China) is a naturalantioxidant extracted from seeds of Apium and apowerful free radical scavenger [168]. It protecteddopamine neurons in a rotenone model for PD[169].

BV-7003 (Bioved Pharmaceuticals, San Jose, CA)is a natural product for the potential treatment of mem-ory loss (Thomson Reuters Pharma, update of July 4,2014).

Caffeoyl-quinic and dicaffeoyl-quinic acidspresent in the water extracts of Centella asiaticaattenuated the reduced expression of nicotinic recep-tors and enhanced apoptosis caused by A� peptide inSH-SY5Y cells [170, 171].

Carnosic acid, a phenolic diterpene compoundfound in the labiate herbs rosemary and sage, sup-pressed A�1-40 and A�1-42 production by activating�-secretase in cultured SH-SY5Y human neuroblas-toma cells and A�1-42 and A�1-43 in U373MG humanastrocytoma cells. Carnosic acid treatment enhancedthe mRNA expression of an �-secretase TACE (tumornecrosis factor-�-converting enzyme, i.e., ADAM17)[172, 173].

Carnosine, a dipeptide, beta-alanyl-L-histidine,naturally occurring in the brain, inhibited A�42 aggre-gation by perturbing the H-bond network in and aroundthe central hydrophobic cluster [174].

Celastrol, a triterpenoid antioxidant compound iso-lated from the Chinese Thunder of God vine (T.wilfordii) reduced A� pathology in a transgenic mousemodel of AD [175]. It inhibited A� production inducedby lipopolysaccharide in vitro [176].

Centella asiatica modulated the aggregationdynamics of �-synuclein [177].

Chunghyuldan (Qingxue-dan in Chinese and Daio-Orengedokuto in Japanese) showed neuroprotectiveeffects through inhibition of microglia-mediated neu-roinflammation in in vitro and in vivo AD-like modelsinduced by A�1-42 toxicity [178].

1,8-Cineole (Eucalyptol) mitigated inflammationin A� intoxicated PC12 cells [179].

Cinnamon extract reduced A� oligomerization andcorrected cognitive impairment in animal models ofAD [180]. Two components of active cinnamon extractare cinnamaldehyde and epicatechin, which inhibitedtau aggregation in vitro [181, 182]. A systematic reviewon the medicinal properties of Cinnamonum zeylan-icum was provided [183].

Cocoa extracts reduced oligomerization ofamyloid-� [878].

Coconut oil attenuated the effects of A� on corticalneurons in vitro [184].

Congrongyizhi Capsule, a Chinese medicine,increased brain activation in amnestic MCI patients[185].

Coriander volatile oil, extracted from Coriandersativum var. microcarpum, ameliorated A�1-42-induced spatial memory impairment in a rat model ofAD [186, 187].

Corilagin (and Geraniin) from Geranium thunbergiishowed BACE1 inhibitory activity in vitro [188].

Corynoxine B, isolated from Uncaria rhyn-chophylla (Miq.) Jacks (Gouteng in Chinese) is aBeclin-1 dependent autophagy inducer. It promoted theclearance of �-synuclein via the Akt/mTOR pathway[189, 190].

Cotinine, a natural metabolite of nicotine, maybe a potential new therapeutic agent against AD[191]. It reduced A� aggregation and improved mem-ory in AD mice [192]. For medicinal chemistry, see[193].

p-Coumaric acid and ursolic acid from corni fruc-tus attenuated A�25-35-induced toxicity through theregulation of NF-κB signaling pathway in PC12 cells[194].

Crocin displayed a protective effect on the amyloidfibril formation of A�42 peptide in vitro [195].

Cryptotanshinone, an active component of themedicinal herb Salvia miltiorrhiza, inhibited A�aggregation and protected SH-SY5Y cells from dam-age by A� [196]. It upregulated �-secretase byactivating the PI3K pathway in cortical neurons [197].The Sun Yat-Sen University (Guangzhou, China) isevaluating a capsule formulation for the potential treat-ment of AD. By September 2013 an IND had beenfiled with the Guangdong Food and Drug Administra-tion (Thomson Reuters Pharma, update of February 11,2014).

�-Iso-cubebenol, a natural compound isolated fromthe Schisandra chinensis fruit, suppressed A�1-42fibril-induced neuroinflammatory molecules in pri-mary microglia via suppression of NF-κB/inhibitor ofκB� and MAPK [198].


Cudrania cochinchinensis attenuated A� protein-mediated microglial activation and promoted glia-related clearance of A� protein [199].

Curcumin showed potent anti-amyloidogeniceffects for AD A� fibrils in vitro and in vivo.Mechanistic insights of curcumin interaction withthe core-recognition motif of A� peptide was pre-sented [200, 201], in particular via activation ofSIRT1 [202]. Curcumin attenuated A�-induced toxic-ity through �-catenin and PI3K signaling [203–205]and by suppression of CRMP-2 hyperphosphory-lation [206]. Curcumin is an A� specific dyein Escherichia coli [207]. Curcumin attenuatedA�-induced tau hyperphosphorylation in humanneuroblastoma SH-SY5Y cells [208] and sup-pressed soluble tau dimers in aged human tautransgenic mice [209]. Curcumin ameliorated mem-ory deficits via neuronal nitric oxide synthase inaged mice [210]. A novel nanocurcumin formula-tion was tested in AD Tg2576 mice [211]. Forcurcumin-decorated nanoliposomes, see [212, 213].Curcumin-gold nanoparticles inhibited A� fibrilgrowth [214].

Trifluoromethylcurcumin (FMeC1), of which theenol form is able to bind to A� aggregates, was usedin 19F nuclear magnetic resonance (NMR) imaging ofthe whole head of Tg2576 mice. FMeC1 also exhib-ited affinity for senile plaques in human brain sections[215].

Curcumin was condensed via an amino-linkerwith an isothiocyanate derivative of GadoliniumIII

diethylenetriaminepentaacetate to yield an effi-cient contrast agent for MRI investigations. Theagent interacted with A� aggregates producingchanges in relaxation rate and fluorescence emission[216].

Cyanidin 3-O-glucoside exerted protective effectson A� peptide-induced cognitive impairments inrats [217].

Cyperus rotundus L. (Cyperaceae) (EECR) ethanolextracts showed protective effects on behavior andcognitive function in a rat model of hypoxia injury[879].

Danshen (Salvia Miltiorrhiza) diversity may helpto defeat dementia [218].

Dendrobium nobile Lindl (EDNLA) is a Chinesemedicinal herb. Alkaloid extracts of it attenuated tauprotein hyperphosphorylation and apoptosis inducedby lipopolysaccharide in rat brain [219].

Dihydromyricetin ameliorated behavioral deficitsand reversed neuropathology of transgenic AD mice[220].

7,8-Dihydroxyflavone, a TrkB receptor agonist andBDNF mimic, reversed memory deficits in a mousemodel of AD [221, 222]. It improved memory consol-idation processes in rats and mice [223–227]. Furthercharacterization is performed at Emory University,Atlanta, GA (Thomson Reuters Pharma, May 22,2014).

Docosahexaenonic and eicosapentaenoic acidsincreased global cognitive performance scores(p < 0.05) in elderly volunteers [228]. For a review onDHA and the aging brain, see [229]. Omega-3 fattyacids do cross the blood-brain barrier [230].

Eicosapentaenoic acid displayed neuroprotectiveeffects against A�-induced impairment of LTP andmemory [231–233]. The beneficial effects of fish-oilcontaining diets can be enhanced by adding other spe-cific nutrients such as vitamins, phospholipids, andselenium [234].

(-)-Epigallocatechin-3-gallate (EGCG; Sunphe-non) present in green tea reduced A�-mediatedcognitive impairment presumably via flavonoid-mediated presenilin-1 phosphorylation, which reducedA� production. New insights into the mechanismwere published recently [235–238]. Surface plasmonresonance imaging of A� aggregation kinetics inthe presence of EGCG and metals was described[239].

Epsilon-viniferin glucoside inhibited the formationof A� toxic assemblies [240].

Ergothioneine and melatonin attenuated oxida-tive stress and protected against learning and memorydeficits in C57BL/6J mice treated with D-galactose[241].

Erythropoietin, intranasally administered, showedpotent protective activity against A� toxicity in theA�25-35 non-transgenic mouse model of AD [242].

ESP-806, the lignin-riched extract of Schisan-dra chinensis fruits, on oral treatment at a dose of100 mg/kg significantly attenuated the A�1-42-inducedmemory impairment in mice [243].

Eucommia ulmoides Oliv. (EUE) aqueous extractsshowed beneficial effects on learning and memoryimpairments in mice [244]. For a review, see [245].

Evodiamine, a natural alkaloid, was the basis formedicinal chemistry efforts. The heptyl carbamate of5-deoxo-3-hydroxyevodiamine exhibited an IC50 of77 nM for BChE and showed pronounced antioxidantproperties [880].

Ferulic acid had disruptive effects on A� fib-rils [246–248]. It inhibited the transition of A�42monomers to oligomers, but accelerated the transitionfrom oligomers to fibrils [249]. It acted as a �-secretase


modulator [250]. It showed protective effects in aA�PP/PS1 transgenic mouse model of AD [251].

Fisetin is a flavonol that belongs to the flavonoidgroup of polyphenols. Via modulation of p25 andinflammatory pathways fisetin maintained cognitivefunction in AD transgenic mice [252].

Flavonoids in AD and neuroinflammation were dis-cussed in depth [253, 254].

FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-di-methoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a synthetic cyclic derivative ofsquamosamide from Annona glabra. It attenuatedA�PP processing and decreased A� production inmitochondria by selectively inhibiting �-secretase[255–257].

Fortasyn Connect (FC; Nutricia Research, Utrecht)is a multi-nutrient diet comprising DHA, eicos-apentaenoic acid, uridine monophosphate, choline,phospholipids, folic acid, vitamins B6, B12, C, and E,and selenium. It reduced AD-like pathology in youngadult A�PPSWE/PS1dE9 mice [258–261].

Gallic acid from grape seed polyphenol extract maybe useful for the treatment of AD [262]. It inhibited A�fibril formation [263].

Gastrodin protected primary cultured rat hip-pocampal neurons against A� peptide-induced neuro-toxicity via ERK1/2-Nrf2 pathway [264]. It alleviatedmemory deficits in a mouse model of AD [265].

Gelsolin, a 82 kDa actin-binding protein that is akey regulator of actin filament assembly and disas-sembly, binds to A� and inhibits its fibrillization. Thelevels of plasma gelsolin are increased by the histonedeacetylase inhibitor trichostatin A [266]. See also Part2, Chapter 2.27. Drugs interacting with HDACs.

Geniposide decreased the level of A�1-42 in thehippocampus of streptozotocin-induced diabetic rats[267]. It ameliorated learning and memory deficits,reduced tau phosphorylation and decreased apoptosisvia the GSK-3� pathway in a streptozotocin-inducedAD rat model [268].

Genistein, the most active molecule of soyisoflavones, inhibited A�25-35-induced neurotoxicityin PC12 cells via a PKC signaling pathway [269, 270].It antagonized inflammatory damage induced by A�in microglia [271].

Geraniin (and Corilagin) from Geranium thun-bergii showed BACE1 inhibitory activity in vitro [188].

Geraniol attenuated �-synuclein expression [272,273].

Ginger root extracts (CT-0109 series of Zingiberofficinale, Cognition Therapeutics, Pittsburgh, PA)effected inhibition of A�42 aggregation [274]. CT-

0093 and CT-0134 prevented A� oligomers’ bindingwith EC50 values of 1.03 and 3.88 �M. CT-013461and CT-013441 reverted the cognitive impairment ina water maze test in transgenic AD mice with a sus-tained improvement for over 5 months at doses of 10and 30 mg/kg/day (Thomson Reuters Pharma, updateof May 12, 2014).

Ginkgo biloba (EGb 761, Tanakan, Tanamin) treat-ment prevented age-related spatial memory deficits ina transgenic mouse model of AD. In a large studyof 2,854 participants over 5 years it was found thatstandardized Ginkgo biloba extract did not reduce therisk of progression to AD compared with placebo[275]. A 20-year follow-up population-based studywas communicated [276]. Catechins and procyanidinsof Ginkgo biloba showed potent activities towards theinhibition of A� aggregation [277].

Ginkgolide B in a novel oil-body nanoemulsion for-mulation achieved memory improvement in a Morriswater maze test in rats [278].

The effects and mechanisms of ginseng and gin-senosides on cognition were reviewed [279].

Ginsen(n)oside Rd, a traditional Chinese medicine,prevented cognitive deficits in a rat model of AD[280–282]. Ginsenoside Rg5 improved cognitive dys-function and A� deposition in STZ-induced memoryimpaired rats [283]. Ginsenoside Rg1 showed pro-tective effects on chronic restraint stress inducedlearning and memory impairments in male mice[284].

Glutathione has an emerging role in AD [285].D-Govadine improved impairments in compro-

mised memory function in delayed response taskspossibly through selective increases in DA efflux inthe frontal cortex [286, 287].

Gramicidin S inhibited A�1-40 fibril formation[288].

Grape-derived polyphenolics from Vitis viniferagrape seeds attenuated cognitive deterioration in amouse model of AD. Ultrastructural alterations ofAD paired helical filaments by grape seed-derivedpolyphenols was studied [289].

Green tea polyphenols protected against okadaicacid-induced acute learning and memory impairmentsin rats [290].

Guarana (Paullinia cupana Mart.), popularly con-sumed in Brazil, was able to prevent protein glycation,A� aggregation, in vitro methylglyoxal, glyoxal, andACR (20 �M)-induced toxicity on neuronal-like cells(SH-SY5Y) [291].

gx-50 derived from Sichuan pepper (ZanthoxylumBungeanum) disassembled A� oligomers, inhibited


A� induced neuronal apoptosis and apoptotic geneexpression and reduced neuronal calcium toxicity[292].

Gypenoside XVII (GP-17) is a novel phytoe-strogen isolated from Gynostemma pentaphyllumor Panax notoginseng. Pretreatment with GP-17(10 �M) for 12 h increased estrogen response ele-ment reporter activity, activated PI3K/Akt pathways,inhibited GSK-3�, induced Nrf2 nuclear translocation,augmented antioxidant responsive element enhanceractivity, upregulated heme oxygenase 1 expressionand activity, and provided protective effects againstA�25-35-induced neurotoxicity including oxidativestress, apoptosis, and autophagic cell death. GP-17 conferred protection against A�25-35-inducedneurotoxicity through estrogen receptor-dependentactivation of PI3K/Akt pathways [293].

Heparin sulfate hexa- to dodecasaccharidesshowed inhibiting properties of �-secretase [294].

HL-0362 (2,2’,4’-trihydroxychalcone; ShanghaiInstitute of Materia Medica of the Chinese Academyof Sciences), isolated from Glycyrrhiza glabra, a newinhibitor of BACE1, efficiently ameliorated memoryimpairment in mice [295]. Structure optimization isongoing (Thomson Reuters Pharma, update of Septem-ber 11, 2013).

Homocysteine exacerbated A� and tau pathologyand cognitive deficits in a mouse model of AD [296].

Homoisoflavonoids may be valuable imagingagents for A� plaques in AD [297].

Hopeahainol A attenuated memory deficits by tar-geting A� in A�PP/PS1 transgenic mice [298].

HP-012 and HP-050 (NeuMed and Il Dong Phar-maceuticals, both Seoul) are natural products andanti-dementia agents with high efficacy, good safetyand tolerability (Thomson Reuters Pharma, updates ofAugust 13, 2013 and August 7, 2013, respectively).

Huanglian-Jie-Du-Tang (HLJDT) is a famoustraditional Chinese herbal formula that has beenwidely used clinically to treat cerebral ischemia.Treatment of N2a mouse neuroblastoma cells stablyexpressing human APP with the Swedish mutation(N2a-SwedAPP) significantly decreased the levels offull-length APP, phosphorylated APP at threonine 668,C-terminal fragments of APP, soluble APP (sAPP)-�and sAPP�-Swedish and reduced the generation of A�peptide in the cell lysates of N2a-SwedAPP [881].

Huperzine A (Cerebra; Shanghai Institute of Mate-ria Medica) is a natural Lycopodium alkaloid found inextracts from Huperzia serrate [299]. It is a potentacetylcholinesterase inhibitor and was launched inChina for the treatment of AD in 1995. Its pharma-

cology, efficacy and safety was extensively described[300–304]. See also Part 2, Chapter 1. Drugs inter-acting with Acetyl- and Butyrylcholinesterase andFig. 1.

HX106N, a water soluble extract prepared froma mixture of the plants Dimocarpus longan, Liriopeplatyphylla, Salvia miltiorrhiza and Gastrodia elata,ameliorated A�25-35-induced memory impairment andoxidative stress in mice [305].

3-Hydroxy-anthranilic acid and L-phospho-serine, two endogenous brain molecules, bound to theHHQK region of A�13-16 and were able to inhibit A�aggregation [306].

3-Hydroxy-butyrate methyl ester provided pro-tection against mitochondrial damages [307].

24(S)-Hydroxy-cholesterol treatment reduced A�production and increased endoplasmic reticulum-resident immature A�PP levels in human neuroblas-toma SH-SY5Y cells and CHO cells stably expressinghuman A�PP [308]. For the diverse functions of 24(S)-hydroxycholesterol in brain, see [309].

2-Hydroxy-docosahexaenoic acid improved per-formance in the radial arm maze test in the 5×FADtransgenic mice model of AD [310] via membrane lipidmodifications [311].

Hydroxy-propyl-�-cyclodextrin showed neuro-protective effects in cell and mouse models of AD[312].

Hydroxy-safflor Yellow A ameliorated homocys-teine induced AD-like pathologic dysfunction andmemory disorders [313]. It inhibited neuroinflam-mation mediated by A�1-42 in BV-2 cells [314] bymodulating the JAK2/STAT3/NF-κB pathway [315].

Hyperforin (vide infra St. John’s Wort).Icariin, a flavonoid isolated from Epimedii herba, is

a phosphodiesterase-5 inhibitor. It improved learningand memory in A�PP/PS1 transgenic mice by stimu-lating NO/cGMP signaling [316].

ID-1201 (Il Dong Pharmaceuticals, Seoul) containsextracts of Melia azedarach (Melia toosendan) andinhibits A� production with neuroprotective effects(Thomson Reuters Pharma, update of July 23, 2014).

IMM-H004, a novel coumarin derivative, protectedagainst A� induced neurotoxicity [317].

Ipriflavone is a synthetic isoflavone which may beused to inhibit bone resorption, maintain bone den-sity and to prevent osteoporosis in postmenopausalwomen. It protected human neuroblastoma SH-SY5Ycells against A�-induced toxicity [318].

Isobavachalcone and bavachinin from PsoraleaeFructus modulate the A�42 aggregation processthrough different mechanisms in vitro [160].


Isorhynchophylline (IRN), the major chemicalingredient of Uncaria rhynchophylla, inhibited GSK-3� activity and activated the phosphorylation ofphosphatidylinositol 3-kinase (PI3K) substrate Akt.IRN improved the A�-induced cognitive impairmentin rats via inhibition of neuronal apoptosis and tau pro-tein hyperphosphorylation [319, 320]. IRN improvedlearning and memory impairments induced by D-galacvtose in mice [882].

Jujuboside A, a neuroprotective agent from semenof Ziziphi Spinosae ameliorated behavioral disordersin an AD mouse model induced by A�1-42 [321].

Juzen-taiho-to is a herbal medicine, which reducedA� burden in a mouse model of AD [322].

Kaempferol prevented lysozyme fibril formation[323].

Kaempferol-3-O-rhamnoside abrogated A� tox-icity by modulating monomers and remodelingoligomers and fibrils to non-toxic aggregates [324].

Lanthionine ketimine ester treatment substantiallydiminished cognitive decline and brain A� peptidedeposition and phospho-tau accumulation in 3x trans-genic AD mice [325].

Laurus nobilis leaf polar extracts showed antiamy-loidogenic efficacy in A�25-35 fragment oxidized cellsystems [326].

Z-Ligustilide, a component of Radix AngelicaSinensis, promoted adult neurogenesis to mediaterecovery from cognitive impairment [327]. The neu-roprotective effects may be due to an upregulation ofKlotho, an aging-suppressor gene [328, 329].

Limonoid compounds are investigated by scien-tists of the Johns Hopkins University (Baltimore,MD) for the potential treatment of acute and chronicneurodegenerative disorders including AD, multiplesclerosis (MS), HD, PD, AIDS related dementia, ALS,stroke, and spinal cord trauma (Thomson ReutersPharma, update of May 29, 2013). Structures were notcommunicated.

Lipoprotein-based nanoparticles, apolipoproteinE-reconstituted high density lipoprotein (ApoE-rHDL), after four weeks of treatment decreased A�deposition, attenuated microgliosis, ameliorated neu-rologic changes and rescued memory deficits in an ADanimal model [330].

Liuwei Dihuang decoction is a well-known pre-scription of traditional Chinese medicine and consistsof six crude drugs including Rehmannia glutinosaLibosch (family: Scrophulariaceae), Cornus officinalisSieb. (family: Cornaceae), Dioscorea oppositifoliaL. (family: Dioscoreaceae), Paoenia ostii (family:Paeoniaceae), Alisma orientale (G. Samuelsson),

Juz (family: Alismataceae) and Poria cocos (Schw.)Wolf (family: Polyporaceae). It significantly improvedcognition deficits of diabetic encephalopathy instreptozotocin-induced diabetic rats [331].

Loganin isolated from Corni fructus showedBACE1 inhibitory activity in vitro [332, 333].

LP-226A1 (Lipopharma Therapeutics, Palma deMallorca) is the lead compound from a series ofpolyunsaturated fatty acid derivatives for the potentialoral treatment of CNS diseases including AD (Thom-son Reuters Pharma, update of December 26, 2013).The structure was not communicated.

Ethanol extract of Magnolia officinalis preventedlipopolysaccharide-induced memory deficiency via itsantineuroinflammatory and antiamyloidogenic effects[334].

Luteolin protected against high fat diet-inducedcognitive deficits in obesity mice [883].

Mannitol is a potent inhibitor of �-synuclein aggre-gation [335].

Marine metabolites showed dual acetyl-cholinesterase and A� aggregation inhibitingproperties [336].

Melatonin in AD was reviewed [337]. It protectedagainst A�-induced impairments of hippocampal LTPand spatial learning in rats [338]. It also improved spa-tial learning and memory in Ts65Dn mice, a model ofDown syndrome [339].

Millettia pulchra polysaccharide showed a pro-tective effect on cognitive impairment induced byD-galactose in mice [340].

N-acetylcysteine showed protective effects againstthe up-regulation of b-amyloidogenesis by 24- and27-hydroxycholesterol [341]. For the impact of N-acetylcysteine on cerebral A� plaques, see [342].

Naringenin from citrus aurantium significantlyreduced A� brain levels in ICV-STZ rats [343].

Naringin from Pomelo peel, a Citrus species,enhanced CaMKII activity and improved long-termmemory in AD mice [344].

Neoechinulin A, an indole alkaloid isolatedfrom marine-derived Microsporum sp., significantlysuppressed the production of neurotoxic inflamma-tory mediators tumor necrosis factor-� (TNF-�),interleukin-1� (IL-1�), interleukin-6 (IL-6), andprostaglandin E2 (PGE2) in activated BV-2 cells [345].

NeurocentRX Pharma (Edinburgh) is investigatinga natural product-based compound for the treatment ofcognitive diseases (Thomson Reuters Pharma, updateof February 18, 2012).

Neuroprotectin D1 (NPD1) is a natural oxidationproduct of DHA. It reduced the A�42 peptide release


from aging human brain cells by down-regulatingBACE1 while activating the �-secretase ADAM10.The downregulation of BACE1 is PPAR�-dependent[346–348]. NPD1 induced homeostatic regulation ofneuroinflammation and cell survival [349].

NeurTriptin (Pharmagenesis, Redwood City, CA)is a prodrug of triptolide (PG-490, Fig. 4), an activeconstituent of PG-27, an immunosuppressive fractionpurified from an extract of the Chinese medical plantTripterygium wilfordii hook F for the potential i.v.treatment of neurodegenerative diseases including ADand PD disease and ALS (Thomson Reuters Pharma,update of February 7, 2013).

Nicotine interacted with the �-sheet of A�16-22 andtransformed it to an �-helical structure, which helped toprohibit the aggregation of A�-protein [350]. Nicotineexerted its neuroprotective effects against A�-inducedneurotoxicity through the Erk172-p38-JNK-dependentsignaling pathway [351]. For medicinal chemistry, see[193].

Nobiletin, a citrus flavonoid, ameliorated cognitiveimpairment, oxidative burden, and hyperphosphoryla-tion of tau in senescence-accelerated mice [352].

Oleocanthal, a phenolic component of extra-virginolive oil, enhanced A� clearance [353].

Oleuropein promoted the �-secretase cleavage ofthe A�PP [354]. Oleuropein aglycon, the main sec-oiridoid phenol present in extra virgin olive oil,counteracted A�42 toxicity in rat brain [355].

Omega-3 fatty acids produced cognitive enhance-ment [356]. They also regulated the interaction ofA�25-35 peptide with lipid membranes [357]. The com-bination of omega-3 fatty acid and �-lipoic acid slowedcognitive and functional decline in AD patients over 12months [75].

Osthole is an O-methylated coumarin found inplants Cnidium monnieri, Angelica archangelica, andAngelica pubescens. It reduced intracellular A� levelsin neural cells, which was associated with decreasedBACE1 protein. It reversed exogenous A�25-35-induced cell viability loss, apoptosis and synapsin-1reduction, which was related to the reestablishmentof phosphorylation of cyclic AMP response element-binding protein (CREB) [358].

Paeoniflorin, a monoterpene glycoside isolatedfrom the aqueous extract of the dry root of Paeo-nia, attenuated A� peptide-induced neurotoxicity byameliorating oxidative stress and regulating the NGF-mediated signaling in rats [359].

Paeonol displayed neuroprotective effects on cog-nition deficits in streptozotocin-induced diabetic rats[360].

Panax ginseng was neuroprotective in a novel pro-gressive model of PD [361].

Pentamethylquercetin protected against diabetes-related cognitive deficits in diabetic rats [362].

L-Phosphoserine and 3-hydroxyanthranilic acid,two endogenous brain molecules, bound to the HHQKregion of A�13-16 and were able to inhibit A� aggre-gation [363].

Piper nigrum fruits methanolic extracts improvedmemory impairment in a rat model of AD [364].

Polyphenols probably interacted with A� throughπ – π stacking interactions via the aromatic aminoacids of A� [365, 366]. Natural phenols protectedagainst pathological conditions associated with A�aggregation [367]. For naturally occurring polypheno-lic inhibitors of amyloid-� aggregation see [884].

Polyunsaturated fatty acids showed properties ofcognitive enhancers [356, 368].

Pomegranate polyphenols inhibited nuclear factorof activated T-cell activity and microglial activation invitro and in a transgenic mouse model of AD [369].

PT-3, a N-benzylcinnamide purified from Pipersubmultinerve, protected rat cultured cortical neuronsfrom A� peptide-induced neurotoxicity [370].

Pterocarpus marsupium (PM, Fabaceae) and Euje-nia jambolana (EJ, Myrtaceae) extracts inhibiteddipeptidyl peptidase-4 and ameliorated streptotocininduced AD in rats [885].

Puerarin, a phytoestrogen isolated from Puerarialobata, attenuated A�-induced cognitive impairment[371, 372]. It decreased A� immunopositive stainingin hippocampus of ovariectomized guinea pigs [373].

Quercetin improved cognitive function in ADtransgenic mice [374]. Oxidized quercetin inhibited�-synuclein fibrillization [375].

Quercetin-O-glucuronide significantly reducedthe generation of A� peptide [376].

Rapamycin, a product of the bacterium Strepto-myces hygroscopicus and a valuable immunosuppres-sant drug, improved after chronic treatment memoryin AD transgenic mice [377].

Rhein lysinate, one of the major bioactive con-stituents in the rhizome of rhubarb, decreased thegeneration of A� in the brain tissues of AD modelmice [378].

Rhus verniciflua bark extract showed cognitive-enhancing effects [379].

Rosa damascena extract induced neurogenesis andsynaptic plasticity in an animal model of AD [380].

Rosamine bearing mild thiol reactivity effectivelyinhibited oligomerization and fibrillization processesof tau in vitro [381].


Rosmarinic acid protected PC12 cells from A�-induced neurotoxicity. The molecular recognition ofthe A�1-42 peptide and rosmarinic acid was investi-gated by NMR [382].

Rutin (3,3’,4’,5,7-pentahydroxyflavone-3-rhamnoglucoside) inhibited A� aggregation andcytotoxicity, attenuated oxidative stress, decreasedthe production of nitric oxide and proinflammatorycytokines [383], activated the MAPK pathway andBDNF gene expression [384] and improved spatialmemory in AD transgenic mice by reducing A�oligomer level [385]. Rutin reduced the elevatedmatrix metalloproteinase-9 level in rats [386].

Salidroside showed neuroprotective effects againstA�-induced oxidative stress in rats [387]. It alsoshowed protective effects in a model of PD [388].

Salvianolic acid A, a polyphenolic derivativefrom Salvia miltiorrhiza bunge, inhibited A� self-aggregation and disaggregated pre-formed fibrils[389].

Salvia sahendica attenuated memory deficits, mod-ulated CREB and decreased apoptosis in A�-injectedrats [390]. It also attenuated acetylcholinesterase activ-ity [391]. A systematic review on clinical trialsassessing the pharmacological properties of salviaspecies on memory, cognitive impairment and AD waspresented [392].

Saposin C, a small heat-stable glycoproteinderived from a common precursor protein prosaposin,protected glucocerebrosidase against �-synuclein inhi-bition [393].

Sarsasapogenin, extracted from traditional Chinesemedicine Rhizoma Anemarrhenae, is evaluated by theShenyang Pharmaceutical University for the potentialtreatment of AD (Thomson Reuters Pharma, update ofAugust 16, 2013).

Sauroine derivatives, i.e., monoacetyl and diacetylsauroine, an alkaloid from Huperzia saururus,improved learning performance of rats [394].

Schisantherin A recovered A�-induced neurode-generation with cognitive decline in mice [395].

Sciadopitysin, the active component from Taxuschinensis, potently inhibited A� aggregation [396].

Scutellarin isolated from Scutellaria barbata andScutellaria lateriflora attenuated neurotoxicity of A�[397, 398].

Silymarin, a flavonoid from the plant Silybummarianum (milk thistle), showed multiple neuropro-tective effects [399]. The beneficial effect of silymarinand its main component, i.e., silibinin, is relatedto its capacity to disaggregate A� plaques and tosuppress A�PP expression [400]. Silymarin amelio-

rated memory deficits in a mouse model of dementia[401].

Souvenaid (Nutricia, Chatel-St-Denis, Switzer-land) is a mix of nutrients including the omega-3fatty acid DHA, uridine monophosphate, and choline,dietary precursors for the synthesis of phospholipids.Two clinical trials, Souvenir I, which lasted 12 weeks,and Souvenir II, which lasted 24 weeks, were con-cluded [402, 403].

Soybean isoflavone ameliorated A�1-42-inducedlearning and memory deficits in rats [404]. It antago-nized the oxidative cerebrovascular injury induced byA�1-42 in rats [405].

Spermine, spermidine, and putrescine (polya-mines) reduced toxicity of soluble A� peptide aggre-gates associated with AD [406].

St. John’s Wort extract (final hyperforin concen-tration 5%) reduced A� accumulation in a doubletransgenic AD mouse model [407].

SuHeXiang Wan, a Chinese traditional medicine,suppressed A�42-induced extracellular signal-relatedkinase hyperactivation [408].

Sulforaphane, a potent antioxidant derived frombroccoli, ameliorated cognitive function in AD micein the Y-maze and in passive avoidance behaviortests [409]. Sulforaphane protected mouse brains fromamyloid-� deposits [886].

Tannic acid interacted with tau peptide by form-ing a hairpin binding motif in addition to hydrogenbonding, hydrophilic/hydrophobic interactions, andelectrostatic interactions [410].

Tanshinones extracted from the Chinese herbDanshen (Salvia Miltiorrhiza Bunge) inhibited A�aggregation, disaggregated A� fibrils and protectedcultured cells from damage by A� [411]. TanshinoneIIA promoted non-amyloidogenic processing of A�PPin platelets via estrogen receptor signaling to phos-phatidylinositol 3-kinase/Akt [887].

Taurine attenuated A�1-42-induced mitochondrialdysfunction by activating SIRT1 in SK-N-SH cells[412]. It showed a therapeutic effect against aluminum-induced impairment on learning, memory and brainneurotransmitters in rats [413].

(+)-Taxifolin from silymarin inhibited the aggrega-tion of A�1-42 [414]. The inhibitory mechanism wasstudied in detail. Taxifolin targets lysine residues inA�42 [415].

Tenuigenin, a Chinese herbal extract, attenuated�-synuclein-induced cytotoxicity by down-regulatingpolo-like kinase 3 [416].

Tetrahydrohyperforin, a semi-synthetic deriva-tive of hyperforin, decreased cholinergic markers


associated with A� plaques and caspase-3 activationin A�PP/PS1 mice [417]. It prevented mitochondrialCa2+ overload after A� challenge in rat hippocampalneurons [418].

2,3,4,4-Tetramethyl-5-methylene-cyclopent-2-enone, a monoterpene necrodane ketone, dose-dependently inhibited BACE-1 in cellular and mousemodels of AD [888].

Thymoquinone present in the essential oil ofthe seeds of Nigella sativa Linn protected culturedrat primary neurons against A�-induced neurotox-icity [419] and cultured hippocampal and humaninduced pluripotent stem cell-derived neurons against�-synuclein-induced synapse damage [420]. An inde-pendent study corroborated these findings [421].

Essential oil compositions of Tragopogon latifoliusvar. angustifolius and Lycopsis orientalis exhibitedmoderate inhibitory activity against acetyl- andbutyryl-cholinesterase enzymes [422].

Tripchlorolide (T4), an extract from the naturalherb Tripterygium wilfordii Hook F, improved age-associated cognitive deficits by reversing hippocampalplasticity impairment in SAMP8 mice [423].

Triptolide (Fig. 4), a biologically active naturalproduct from Tripterygium wilfordii, protected neuronsby inhibiting A� production and by inhibiting CXCR2activity [424].

Troxerutin, a bioflavonoid, significantly improvedthe synaptic failure induced by A� peptide [425].

Ursolic acid and p-coumaric acid from corni fruc-tus attenuated A�25-35-induced toxicity through theregulation of NF-κB signaling pathway in PC12 cells[194].

Valeriana amurensis improved A�1-42 inducedcognitive deficits in mice [426]. The neuroprotec-tive active constituents of Valeriana amurensis weredescribed [889].

Viniphenol A, a resveratrol hexamer from Vitisvinifera stalks, showed protective effects against A�induced toxicity in PC12 cells [427].

Vitisinol C from Vitis vinifera grapevine shootsextracts exerted a significant activity against A� aggre-gation [428].

Walnut extract inhibited the fibrillization ofamyloid-� protein [890] and protected againstamyloid-� peptide-induced cell death and oxidativestress in PC12 cells [891]. Dietary supplementationof walnuts improved memory deficits in a transgenicmouse model of AD [892].

Xanthoceraside, a triterpenoid saponin, rescuedlearning and memory deficits through attenuatingamyloid-� deposition and tau hyperphosphorylation

in APP mice [893]. It inhibited pro-inflammatorycytokine expression in A�25-35/IFN-�-stimulatedmicroglia [894] and attenuated tau hyperphosphoryla-tion and cognitive deficits in intracerebro-ventricular-streptozotocin injected rats [895].

Yokukansan (TJ-54), a traditional Japanese herbalmedicine, was tested in clinics for potential anti-dementia effects [429]. Spatial memory was improvedin a rat model of early AD [430].

Yuzu (citrus junos Tanaka) extract prevented cogni-tive decline in A� infused rats [431].

The development of AMR-109 (ultra-pure eicos-apentanoic acid, Amarin Corporation), AX-00111(Axonal Consultoria Tecnologica), polyphenolderivatives (Pharma Eight) and of PTX-200 (Phytrix)was terminated.

NOOTROPICS (“DRUGS WITHOUTMECHANISM”)

In this chapter compounds are described whosemechanism(s) of action are unknown. Initiation of clin-ical trials was based on positive effects on impairedbrain functions in experimental animals after proof ofgood tolerability.

TRI-102-ADD-001 (Tris Pharma, Monmouth Junc-tion, NJ) is a small molecule therapeutic for thepotential treatment of ADHD. In March 2014, a ran-domized, double-blind, parallel-assigned, Phase IIItrial was initiated in ADHD patients (expected n = 90)in the US to evaluate the safety and efficacy (Thom-son Reuters Pharma, update of March 20, 2014). Thestructure was not communicated.

LND-101001 (Lupin, Mumbai, India) is a smallmolecule therapeutic for the potential treatment of AD.In October 2013 a randomized, double-blind, placebo-controlled, parallel group, comparative, multicenterPhase II study was initiated in Poland and Lithuania inpatients (n = 171) with mild to moderate AD (Thom-son Reuters Pharma, update of January 28, 2014). Thestructure was not communicated.

PXT-864 (Pharnext, Ile-de-France) is a drug for thepotential treatment of AD and age-related memory loss(ARML) in Phase II clinical trials since December2013 in France (Thomson Reuters Pharma, update ofJune 30, 2014). The structure was not communicated.

ASP-3662 (Astellas Pharma, Tokyo) is in Phase Iclinical trials in Japan for the potential oral treatmentof AD since May 2013 (Thomson Reuters Pharma,update of May 12, 2014). The structure was notcommunicated.


GSK-2981710 (GSK) is a medium chain triglyc-eride in Phase I clinical trials in the UK since December2012 (Thomson Reuters Pharma, update of January 3,2014). The structure was not disclosed.

JNJ-54861911 (Janssen Research & DevelopmentLLC, Raritan, NJ) is investigated for the potential oraltreatment of AD. In May 2013, a Phase I trial was ini-tiated in Belgium in healthy subjects (expected n = 40)(Thomson Reuters Pharma, update of June 5, 2014).The structure was not communicated.

KU-046 (Kareus Therapeutics, Atlanta, GA andConnexios Life Sciences, Bangalore, India) is a potentNADPH oxidase inhibitor and significantly reducedsuperoxide production in vitro and improved cog-nitive function in both rat and mouse models. InJanuary 2013, an IND was approved by the FDA anda randomized, double-blind, placebo-controlled two-part, safety, tolerability and pharmacokinetics Phase Itrial was initiated in the US with healthy volunteers(expected n = 54) (Thomson Reuters Pharma, updateof June 9, 2014). The structure was not disclosed.

MRZ-99030 (Merz, Frankfurt am Main) is anophthalmic solution for the potential treatment of glau-coma in Phase I clinical trials since October 2012 inGermany (Thomson Reuters Pharma, update of June5, 2014). The structure was not communicated.

Pentylenetetrazole (pentetrazol, PTZ, BTD-001;Balance Therapeutics, San Bruno, CA) is investigated

for the potential treatment of cognitive impairmentin Down’s syndrome. In August 2012, a Phase Ib,double-blind, randomized, placebo-controlled, paral-lel group, safety, tolerability, preliminary efficacy andpharmacodynamic study of was initiated in youngadults and adolescents (expected n = 90) with Down’ssyndrome in Australia and New Zealand (ThomsonReuters Pharma, update of March 31, 2014).

PF-06412562 (Pfizer) is in Phase I clinical trials inhealthy subjects (expected n = 38) for the potential oraltreatment of cognitive disorders since August 2013 inthe US (Thomson Reuters Pharma, update of May 12,2014). The structure was not communicated.

There are many nootropic agents in preclinical eval-uation (in alphabetical order):

ARO-01 (Applied Research using OMIC SciencesSL, AROMICS, Barcelona) is a compound for thepotential treatment of AD (Thomson Reuters Pharma,update of September 27, 2013). The structure was notdisclosed.

CPC-001, CPC-201, and CPC-252 (Chase Phar-maceuticals, Washington, DC) are compounds for thepalliative treatment of AD and PD (Thomson ReutersPharma, update of May 12, 2014). The structure wasnot communicated.

D-110 and D-180 (Envoy Therapeutics, Jupiter, FL,a subsidiary of Takeda Pharmaceuticals, Osaka) arecompounds that target a protein specifically expressed

Fig. 5. Two nootropics, a peptide and three amyloid-� aggregation inhibitors.


in D2 receptor-expressing neurons in brain striatumand are designed to mimic deep brain stimulation forthe potential oral treatment of PD (Thomson ReutersPharma, update of February 7, 2013). The structurewas not disclosed.

Gre-213 (Grespo, Stockholm) is an oral combina-tion of two undisclosed compounds for the potentialtreatment of CNS disorders including MCI and ADand PD (Thomson Reuters Pharma, update of March28, 2014). The structures were not disclosed.

IPR-088 (Iproteos, Barcelona) is a peptidomimeticfor the potential oral treatment of cognitive impair-ment associated with schizophrenia (Thomson ReutersPharma, update of November 22, 2013). The structurewas not disclosed.

IRL-752 (Integrative Research Laboratories Swe-den, Goteborg) is a cortical enhancer for the potentialoral treatment of behavioral and psychological symp-toms of dementia and/or attention disorders (ThomsonReuters Pharma, update of November 19, 2013). Thestructure was not disclosed.

JBD-401 (Jinis Biopharmaceuticals, Wanju, SouthKorea) is a small molecule therapeutic for the poten-tial treatment of dementia (Thomson Reuters Pharma,update of March 17, 2014). The structure was notcommunicated.

KH-110 (Chengdu Kanghong Pharmaceuticals,China) is a small molecule therapeutic for the poten-tial treatment of AD (Thomson Reuters Pharma,update of October 24, 2013). The structure was notcommunicated.

MK-8189 (Merck) is investigated for the potentialtreatment of schizophrenia. In July 2014 a Phase I trialwas planned (Thomson Reuters Pharma, update of July14, 2014). The structure was not communicated.

P7C3-A20 (University of Texas, SouthwesternMedical Center, Dallas, TX; Fig. 5) is a small moleculeneuroprotectant for the potential treatment of PD, HD,and ALS. In a rat model of age-related cognitivedecline and in a zebrafish model of retinal degenerationit demonstrated protective effects. The neuroprotectiveefficacy after TBI was described [432]. For the synthe-sis, see [433] (Thomson Reuters Pharma, update ofDecember 10, 2013).

PK-048 (PharmaKure, a spin out from the Univer-sity of Manchester; Fig. 5) is a neuroprotectant at anunspecified drug target for the potential treatment ofAD (Thomson Reuters Pharma, update of April 2,2014).

Q-50 and Q-134 (Avidin Biotechnology, Szeged,Hungary) are quinolone analogues, called kinolols, forthe potential treatment of anxiety and AD (Thomson

Reuters Pharma, update of January 22, 2014). Thestructures were not communicated.

SPO-1112 (Seoul Pharma, Siheung, South Korea) isa nootropic agent for the treatment of dementia (Thom-son Reuters Pharma, update of June 7, 2013). Thestructure was not communicated.

The development of alaptide (VUFB), AQW-051(Novartis; Phase II trials for treatment of schizophreniaand PD are ongoing; Thomson Reuters Pharma, updateof February 4, 2014), AVN-397 (Avineuro Pharmaceu-ticals; Phase II trials for the treatment of anxiety areongoing; Thomson Reuters Pharma, update of October22, 2012), DWJ-209 (Daewoong Pharmaceuticals; theinvestigations for a potential use in pancreatic and lungcancer continue; Thomson Reuters Pharma, update ofMay 21, 2014), JWB1-84-1 (Medical College of Geor-gia; [434, 435]), KTX-0101 (KetoCytonyx), LSL-001(Laboratoire S. Lasnier), MRZ-99030 (Merz; clini-cal evaluation for the indication glaucoma continues;Thomson Reuters Pharma, update of December 31,2013), OG-635 (Oryzon Genomics), PN-403 (Well-stadt Therapeutics) and procain (Samaritan) wasterminated.

PEPTIDES

Davunetide (intranasal, AL-108, NAP, Tel AvivUniversity, previously Allon Therapeutics, Vancouver,BC) is an 8-amino acid peptide (NAPVSIPQ) derivedfrom the activity-dependent neuroprotective protein.Phase II clinical trials were initiated for the potentialtreatment of AD and schizophrenia in the US and forage-related macular degeneration, glaucoma, autism,cognitive disorders, and motor neuron disease in Israelin November 2013. The effects of davunetide on cog-nition and functional capacity in schizophrenia weredescribed [436] (Thomson Reuters Pharma, update ofMay 26, 2014). Davunetide is not an effective treatmentfor progressive supranuclear palsy [35].

NNZ-2566 (Neuren Pharmaceuticals, Auckland,NZ; Fig. 5) is an analogue of glypromate with an addi-tional �-methyl-group on the proline moiety, whichresulted in an improved half-life and better oralbioavailability. In March 2012, a randomized, double-blind, placebo-controlled Phase I study was initiatedin healthy volunteers (n = 32) in Australia. Potentialindications are mild TBI, Rett syndrome, PD and AD[437–439, 440]). In March 2013, a Phase II trial for thetreatment of Rett syndrome in adolescent/adult patientswas initiated in the US. Neuren received orphan drugdesignation from the FDA for NNZ-2566 in fragile X


syndrome. A Phase II trial for fragile X syndrome wasinitiated in January 2014 in the US. Neuren is alsodeveloping a formulation for intravenous infusion forsevere TBI. A Phase II trial for TBI began in May 2010in the US in collaboration with the US Army (ThomsonReuters Pharma, update of June 5, 2014).

There are many peptides in preclinical evaluation forthe potential treatment of AD (in alphabetical order):

acALY-18 (Therimunex, Doylestown, PA) isa synthetic peptide moiety of 1-peptidyl-2,3-diacylglyceride (pDAG), an immunostimulatory agentfirst isolated from Capra hircus (goat) serum as aninjectable formulation for the potential prevention andtreatment of AD [441] (Thomson Reuters Pharma,update of September 13, 2013).

Amphiphile (PA) with a laminine epitope IKVAV(IKVAV-PA) can be triggered into three-dimensionalnanostructures in vivo. Injection of IKVAV-PA intothe hippocampus of transgenic AD mice signifi-cantly improved cognitive impairment accompaniedby enhanced neurogenesis in the hippocampus [442].

Amyloid-� interacting peptides (University ofEssex, Colchester, UK) were generated by anintracellular protein-fragment complementation assayapproach [443].

BN-201 (G-79; Bionure, Barcelona) is a peptide forthe potential treatment of MS, ALS, AD, PD, glau-coma, and neuromyelitis optica. Oral, i.v., and topicalformulations are evaluated (Thomson Reuters Pharma,update of May 28, 2014).

CB-102, HNG6FA, and S14G-humanin (S14G-HN) (CohBar, Pacific Palisades, CA) are humaninanalogues, a peptide encoded within the mitochondria,for the potential treatment of AD and type 2 diabetesmellitus (Thomson Reuters Pharma, update of May 24,2013).

Colostrinin-derived peptides (ReGen Therapeu-tics, London) are evaluated for the potential treatmentof neurodegenerative diseases such as AD and forthe potential treatment of obesity (Thomson ReutersPharma, updates of October 22, 2012). Structures werenot communicated.

D-Ala2GIP (glucose-dependent insulinotropicpolypeptide) facilitated synaptic plasticity andreduced plaque load in aged wild type mice and in anAD A�PP/PS1 mouse model [444, 445].

Ferrocene-Gly-Pro-Arg conjugates showedinhibitory effects on A�1-42 fibrillogenesis and A�induced cytotoxicity in vitro [446].

FGL (FG loop; ENKAM Pharmaceuticals, Copen-hagen, DK) is a peptide neural cell adhesion molecule(NCAM) mimetic for the potential treatment of AD and

stroke (Thomson Reuters Pharma, update of August19, 2013).

G33LMVG37, the sequence of the glycine zipperregion of the C-terminal of A� inhibited the A�-induced synaptotoxicity [447].

Ghrelin was used as a neuroprotective and pallia-tive agent in AD and PD [448]. It successfully rescuedthe abnormality of neurogenesis in 5×FAD mice[449].

�-Glutathione (psi-GSH) is a stable glutathioneanalogue, in which the amide bond is replaced by a ure-ide linkage. It crossed the blood-brain barrier via theglutathione active uptake machinery, protected cellsagainst chemical oxidative insult and lowered the cyto-toxicity of A� [450]. Researchers of the University ofMinnesota (Minneapolis, MN) showed that the restora-tion of glyoxalase enzyme activity precluded cognitivedysfunction in AD mice [451].

Leptin inhibited A� protein degradation througha decrease of neprilysin expression [452] and inhib-ited amyloid-� protein fibrillogenesis [897]. Leptingene therapy attenuated neuronal damages evokedby A� and rescued memory deficits in A�PP/PS1mice [453]. Leptin influences many central processesincluding cognition [454]. The dysregulation of leptinsignaling in AD was reviewed [455]. Leptin pre-vented hippocampal synaptic disruption and neuronalcell death induced by A� [456]. Leptin regulated A�production via the �-secretase complex [457]. Lep-tin and ghrelin prevented hippocampal dysfunctioninduced by A� oligomers [458, 459]. Lower lep-tin plasma levels were observed in people with MCIor with AD than in subjects with normal cognition[460]. Scientists of Neurotez (Bridgewater, NJ) areinvestigating leptin as an A� synthesis and tau phos-phorylation inhibitor for the potential treatment ofAD (Thomson Reuters Pharma, update of May 22,2014).

Min-301 (NRG-101; Minerva Neurosciences Cam-bridge, MA following the acquisition of Mind-NRG,Geneva, Switzerland, previously under license fromProteoSys, Mainz, Germany) is an injectable neureg-ulin peptide for the potential treatment of PD, AD, andschizophrenia (Thomson Reuters Pharma, update ofApril 17, 2014).

Neu-AZ1 (Neurim, Tel Aviv) is a CD44-derivedoctapeptide for the potential treatment of AD. Neu-AZ1 gave a full protection from A�1-42 by dailys.c. administration in a Morris water maze and newobject recognition assays (Thomson Reuters Pharma,update of May 29, 2014). The structure was notcommunicated.


Neuropeptide Y prevented spatial memory deficitsand oxidative stress following A�1-40 administration inmice [461]. The roles of neuropeptides including neu-ropeptide Y in learning and memory were discussed[462].

NRP-2945 (formerly called NNZ-4945; CuroNZ,Auckland NZ under license from Neuren Pharmaceuti-cals, Auckland NZ) is an 11-mer neuronal regenerationpeptide (NRP) for the potential treatment of MSand motor neuron disease [463] (Thomson ReutersPharma, update of February 4, 2014). The structurewas not communicated.

P-8 (Cenna Biosciences, San Diego, CA) isan eight amino acid peptide for the potentialintranasal treatment of AD (Thomson Reuters Pharma,update of May 29, 2013). The structure was notcommunicated.

A synthetic peptide corresponding to a region of thehuman pericentriolar material 1 (PCM-1) proteinbinds A�1-42 oligomers [464].

Rattin, a specific derivative of humanin in rats, pro-tected against A�-induced deficits of spatial memoryand synaptic spasticity in rats [465, 466].

RGX-100 (Cortica Neuroscience, Wilmington, DEfollowing its merger with RemeGenix, Bethesda, MD)is an A� production-inhibiting BRI2-derived pep-tide for the intranasal administration to AD patients[467–475]. Transgenic BRI2-A� mice showed nor-mal cognition [476]. The role of BRI2 in dementiawas discussed [477] BRI2-BRICHOS is increasedin human amyloid plaques in early stages of AD[898]. (Thomson Reuters Pharma, update of January9, 2013).

Tet-1EGCG@Se is an EGCG stabilized seleniumparticle preparation coated with Tet-1 peptide, a syn-thetic selenium protein analogue, which reduced A�aggregation and cytotoxicity [478].

TFP-5 (National Institute of Neurological Disor-ders and Stroke, NINDS, Bethesda, MD) is a modifiedtruncated peptide derived from p35, an activator ofCdk5, for the potential treatment of AD [479] (Thom-son Reuters Pharma, update of May 10, 2013). Thestructure was not communicated.

The development of AL-408 (Allon Therapeutics),Alzimag (IMAGENIUM), Colostrinin (ReGen Ther-apeutics), KIBRA pathway modulators (Amnestixand SYGNIS Pharma; [480–482]), metallothionein(Neurosciences Victoria and University of Tasma-nia; [483]), NNZ-4921 (CuroNZ under license fromNeuren Pharmaceuticals), peptide therapeutics forAD (Cenna Biosciences) and of SEN-304 (Senexis;[484]) was terminated.

DRUGS PREVENTING AMYLOID-�AGGREGATION

The role of A� in the regulation of memory wasdiscussed [485]. Low concentrations of A� are nec-essary for LTP expression and memory formation.Cyclic adenosine monophosphate (cAMP) controlsA�PP translation and A� levels [486]. It is the cere-bral microvascular rather than the parenchymal A�pathology, which promoted early cognitive impairment[487]. The molecular and neurophysiological mecha-nisms of A� and cognition in AD were outlined [488].Amyloid burden correlated with cognitive decline inAD patients presenting with aphasia [489]. FibrillarA� correlated with preclinical cognitive decline [490].Cognitive decline in adults with high A� load was eval-uated [491]. A� deposition was estimated to take 19years in an almost linear fashion and slowed towards aplateau [492, 493]. The case for soluble A� oligomersas a drug target in AD was made [494–496]. Also N-truncated A�4-42 forms stable aggregates and inducedacute and long-lasting behavioral deficits [497].

The inhibition and reversion of A� misfolding andaggregation is an approach, which has been followedup by many research groups during years. Excellentreviews dealing with this subject were published (inchronological order) 2012: [498], 2013: [499–502],2014: [503, 504].

ALZ-801 (BLU-8499, NRM-8499; Alzheon, Lex-ington, MA under license from Bellus Health,formerly Neurochem, Laval, Quebec) is a prodrugof tramiprosate. It was evaluated in a single-center,randomized, double-blind, placebo-controlled PhaseI study in 84 young and elderly healthy subjectsto assess safety, tolerability and pharmacokinetics,which started in March 2010. It showed improvedgastrointestinal tolerability and lower inter-individualvariability of drug exposure compared to compara-ble doses of tramiposate (Thomson Reuters Pharma,update of May 7, 2014).

There are many A� aggregation inhibitors in pre-clinical evaluation (in alphabetical order):

8-Hydroxyquinolines (Whitehead Institute forBiomedical Research, Cambridge, MA) including clio-quinol are evaluated as A� inhibitors for the potentialtreatment of AD [505, 506] (Thomson Reuters Pharma,update of March 5, 2014). For a combination of resver-atrol and clioquinol see [899].

ACI-260 (AC Immune, Lausanne, Switzerland) is asmall molecule A� �-sheet formation inhibitor devel-oped using the company’s Morphomer technology forthe potential treatment of glaucoma (Thomson Reuters


Pharma, update of January 21, 2014). The structure wasnot communicated.

ACI-812 (AC Immune, Lausanne, Switzerland) isa small molecule that inhibited aggregation of the �-sheet form of A� peptide to oligomeric and fibrillarspecies developed using the company’s Morphomertechnology for the potential treatment of AD [507].The concept of a donor-acceptor-donor hydrogen bondpattern complimentary to that of the �-sheet of A�42was first investigated by Schrader and coworkers [508](Thomson Reuters Pharma, update of December 4,2013). The structure was not communicated.

ALZT-OP1 and ALZT-OP2 (AZTherapies,Boston, MA) are combinations of repurposed FDAapproved drugs delivered using the company’s ALZT-patch, which acts by inhibiting the aggregation of A�peptides for the potential treatment of AD and MCI(Thomson Reuters Pharma, update of May 26, 2014).Structures were not communicated.

A� aggregation inhibitors (Baxter Healthcare,Deerfield, IL and the University of Illinois at Urbana-Champaign) are peptide-based inhibitors coupled topolymer backbones for the potential treatment of AD(Thomson Reuters Pharma, update of November 19,2013). Structures were not communicated.

A� aggregation-mitigating peptide analogues(Louisiana State University, Baton Rouge, LA) demon-strated a better in vitro and in vivo A� fibrillogenesisinterference compared to previously existing peptideanalogs (Thomson Reuters Pharma, update of Novem-ber 28, 2013). Structures were not communicated.

Amyloid-� inhibitors (BSIM2, a spin-off companyfounded in 2011 of the University of Coimbra, incollaboration with the University of Leeds) for thepotential treatment of AD (Thomson Reuters Pharma,update of July 25, 2014). No structures were disclosed.

A� oligomer cellular prion protein bindinginhibitors (AstraZeneca under a sublicense from Axe-rion Therapeutics, Branford, CT under license fromYale University, New Haven, CT) are interacting withthe cellular prion protein (PrPC), the high affinityreceptor for A� oligomers [509, 510]. Prion proteinalso interacts with mature A� fibrils [511]. This pro-gram was selected for support by the National Institutesof Health Blueprint Neurotherapeutics Network Pro-gram (Thomson Reuters Pharma, update of September27, 2013). No structures were disclosed.

A� oligomer inhibitors (Virginia CommonwealthUniversity, Richmond, VI) are investigated for thepotential treatment of AD (Thomson Reuters Pharma,update of December 26, 2013). No structures weredisclosed.

APP-E2 modulators (Fritz-Lipmann-Insitut EV Leibniz-Institut fur Altersforschung, Jena andAscenion, Munich) are therapeutics targeting the extra-cellular domain 2 of A�PP for the potential preventionand treatment of AD (Thomson Reuters Pharma,update of February 12, 2013). Structures were notcommunicated.

A�PP synthesis inhibitor (National Institute ofAging, Bethesda, MD) is evaluated for the potentialtreatment of neurological diseases including AD anddementia (Thomson Reuters Pharma, update of May10, 2013). The structure was not disclosed.

Beta-Breaker Dipeptides (BBDP) reversed theaggregation of A�1-40 self-assembly [512].

Carmustine, a �-chloro-nitrosourea compoundused as an alkylating agent in chemotherapy, signif-icantly reduced A� plaque burden in an AD mousemodel [513].

Ceftriaxone, a �-lactam antibiotic, binds with goodaffinity to �-synuclein and blocked its in vitro polymer-ization [514].

D1 and D3 peptides (Fritz-Lipmann-Institut E VLeibniz-Institut fur Altersforschung, Jena and Asce-nion, Munich) specific to A�42 plaques are investigatedfor the potential treatment of AD (Thomson ReutersPharma, update of December 13, 2012). The structureswere not communicated.

D3 (University of Duesseldorf) is an A� oligomerdirected 12-mer D-enantiomeric peptide with anadditional lysine at the C-terminal bearing the flu-orescent ligand FITC. D3 removed A� deposits,reduced inflammation and improved cognition in agedA�PP/PS1 double transgenic mice [515–517].

Decapeptide RYYAAFFARR inhibited A� aggre-gation because of its high affinity for A�11-23[518].

A dual-functional nanoparticle drug delivery sys-tem based on a PEGylated poly lactic acid polymer towhich TGN, a peptide targeting the blood-brain barrierand QSH, a peptide with high affinity for A�1-42 effi-ciently targeted amyloid plaques in the brains of ADmice [519].

Epigenetix (Montreal) is investigating smallmolecule modulators of amyloidogenesis for thepotential treatment of AD (Thomson Reuters Pharma,update of July 18, 2014). Structures were notdisclosed.

GAG/carbohydrate compounds (ProteoTech,Kirkland, WA) are glycosaminoglycan modulatorsfor the potential treatment of AD (Thomson ReutersPharma, update of May 6, 2014). Structures were notdisclosed.


Gismo Therapeutics (USA) investigates gly-cosaminoglycan interacting small molecules(GISMO), which inhibit the uptake of HS-GAG/A�protein aggregates via endo-lysosomal route forthe potential treatment of AD (Thomson ReutersPharma, update of March 6, 2014). Structures werenot disclosed.

Gold nanoparticles inhibited amyloid-like fibrillo-genesis [520].

4-Hydroxy-indole derivatives (Tel Aviv Uni-versity) inhibited amyloid fibril formation andcytotoxicity [521]. 4-HI treated 5-month old miceshowed a full behavioral recovery of cognitive abilities.

ITH12410/SC-058 (University of Madrid, Fig. 5)protected SH-SY5Y cells against the loss of cell via-bility elicited by amyloid-� [900].

K-114 (trans,trans)-1-bromo-2,5-bis(4-hydroxysty-ryl)benzene) inhibited A� aggregation and inflam-mation in vitro and in vivo in AD transgenic mice[522].

KHG-26377 (2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride; University of UlsanCollege of Medicine, Seoul, Fig. 5) significantlyreduced A�25-35-induced primary cortical neuronalcell neurotoxicity [901]. The compound also sup-pressed glutamate-induced excitotoxicity [902],produced anti-inflammatory effects [903] and showedneuroprotective effects against oxidative stress [904].

ML (Multifunctional Ligand, University of Michi-gan, Ann Arbor, MI, University of California SantaBarbara, CA, Seoul National University and UlsanNational Institute of Science and Technology; Fig. 5)is a molecule, which combines structural elementsof A� aggregation inhibition, metal chelation, reac-tive oxygen species regulation, and antioxidant activitywith good water solubility and brain permeability[523].

1,4-Naphtoquinone-2-yl-L-tryptophan (NQTrpand Cl-NQTrp, Tel Aviv University) inhibited A� self-assembly and reduced its toxicity. Atomic and dynamicinsights were communicated [524–526] (ThomsonReuters Pharma, update of January 22, 2014).

Polyfluorinated bis-styrylbenzenes are A� plaquebinding ligands [527].

Poly-4-styrenesulfonate acted as an inhibitor ofA�40 fibril formation [528].

Razoxane (National Institute of Aging, Bethesda,MD) reduced A�PP and A� (Thomson ReutersPharma, update of July 19, 2013).

Selenium compounds prevented A� peptide neu-rotoxicity in rat primary hippocampal neurons[529].

SG1 is a novel pseudopeptidic A� aggregationinhibitor designed to bind at the A� self-recognitionsite [530].

A Tetrachloro-Platinum complex on a 8-(1H-benzoimidazol-2-yl)-quinoline (8-BQ) scaffold wasshown to reduce the number of A� plaques by 29%after an oral treatment for 18 weeks of Tg2576 micewith a daily dose of 15 mg/kg [531]. For a review, see[532].

Transthyretin-derived peptides acted as A�inhibitors [533].

Tricyclic pyrones (Kansas State University, Man-hattan, KS) decreased the aggregation of A� plaques(Thomson Reuters Pharma, update of February 15,2013). Structures were not communicated.

TRV-217 and TRV-1387 (Treventis, Bernville, PA),dual tau/A� oligomerization inhibitors, are orallybioavailable, metabolically stable drugs with high per-meability through the blood-brain barrier (ThomsonReuters Pharma, update of September 20, 2013). Struc-tures were not communicated.

University of Arkansas scientists found a series ofpeptoids modulating the aggregation of A�40 [534](Thomson Reuters Pharma, update of May 8, 2014).

University of California San Diego scientists areinvestigating inhibitors of ion channel activity of A�oligomers for the potential treatment of AD (ThomsonReuters Pharma, update of July 11, 2013). Structureswere not communicated.

NPT-014 and NPT-088 (NeuroPhage Pharmaceuti-cals, Cambridge, MA) are second generation IgG4-Fcfusion proteins using general A� interaction motif(GAIM) technology for the potential treatment of neu-rodegenerative disorders, such as AD, PD, and HD(Thomson Reuters Pharma, updates of November 29,2013 and of April 23, 2014, respectively).

Excellent papers on A� aggregation inhibitors fromuniversities were presented: 2013: [535–542], 2014:[543–545, 922].

Excellent papers on theoretical calculations on A�-aggregation inhibitors were published: 2013: [546],2014: [547–550].

The development of A� inhibitor (Icogenex),BMS-869780 (Bristol-Myers Squibb), caprospinol(SP-233; Samaritan Pharmaceuticals; [551–554]),CLR-01 (a molecular tweezer, University of Duisburg-Essen, Rensselaer Polytechnic Institute, UCLAand Clear Therapeutics, a spin-off from UCLA;[555–566]), DBT-1339 (Medifron), IPS-04001 andIPS-04003 (InnoPharmaScreen, Asan, South Korea),KMS-88 series (Hanmi Pharmaceutical, the KoreaInstitute of Science and Technology and Seoul


National University; [567–569]), SEN-1500 and SEN-1576 (Senexis; [570, 571]) and SP-08 (SamaritanPharmaceuticals) was terminated.

Ligands Interacting with amyloid-β

Since the discovery of the 11C-PiB-PET ligandtremendous progress has been made in the develop-ment of new PET ligands. The development of PET A�imaging agents was described [572–574]. Appropriateuse criteria for amyloid PET studies were proposed[575–578]. Amyloid tracers detected multiple bindingsites in AD brain tissue [579]. Via molecular dynam-ics simulations a common binding mode for imagingagents was identified [580]. A summary of primaryfindings and conclusions on A� PET in the diagnosticevaluation of AD was presented [581]. For excel-lent reviews, see [582–584]. A selective PET templatemethod for spatial normalization of amyloid imagingwith 11C PiB was presented [905].

18F-Florbetapir (18F-AV-45; Amyvid; AvidRadiopharmaceuticals, Philadelphia, PA, a subsidiaryof Eli Lilly, under license from the University ofPennsylvania) was approved by FDA as a PETimaging agent to estimate A� neuritic plaque densityin patients with cognitive impairment on April 6,2012 [585] (for the structure, see [7]). Florbetapirwas approved in the EU on January 15, 2013. Thehighlights on the European marketing approval weredescribed [586] Florbetapir imaging allows analysesof white and grey matter in early AD patients [906].A comparison of amyloid PET imaging with 11C-PiB,18F-florbetapir and 18F-flutemetamol was presented[907] (Thomson Reuters Pharma, update of May 20,2014).

18F-Flutemetamol (18F-Vizamyl; AH-110690,18F-6-OH-BTA-1; 18F-GE-067; [18F]-PIB; GE-067;Uppsala Imanet, a part of GE Healthcare, Chalfont,UK and the Universities of Pittsburgh and Uppsala)was approved by FDA on October 28, 2013 (for thestructure, see [7]). By April 2014 GE Healthcare sub-sidiary and licensee Nihon Medi-Physics planned tofile an application in Japan (Thomson Reuters Pharma,update of June 4, 2014).

18F-Florbetaben (Neuraceq, 18F-BAY 94-9172;18F-AV-1/ZK; Piramal Healthcare, Mumbai, Indiafrom an asset acquisition from Bayer under licensefrom Avid Pharmaceuticals, Philadelphia, PA and theUniversity of Pennsylvania) received marketing autho-rization from EMA for the detection of A� for thediagnosis of AD in February 2014 (for the structure,see [7]). FDA approved Neuraceq for PET imaging

of A� neuritic plaque density on March 20, 2014 A�imaging with 18F-florbetaben in prodromal AD waspublished [908] (Thomson Reuters Pharma, update ofJune 11, 2014).

18F-NAV-4694 (AZD-4694; Navidea Biopharma-ceuticals, Dublin, OH, formerly Neoprobe Corporationunder license from AstraZeneca; Fig. 6) is an i.v. PETligand for the potential imaging of A� depositionsin AD patients [587]. A head-to-head comparison of11C-PiB and 18F-NAV-4694 for A� imaging in agingand dementia was reported [588]. In June 2013 anon-randomized, open label, multicenter, single groupassignment, global Phase III trial was initiated in theUS in patients with AD (expected n = 275) to evaluatethe safety and efficacy of NAV-4694 for detection ofcerebral A� with and without diagnosis of dementiacompared with post mortem histopathology (Thom-son Reuters Pharma, update of June 12, 2014). For thesynthesis, radiolabeling and in vivo pharmacokineticevaluation of 11C-AZD-4694 in nonhuman primates,see [589].

Aftobetin (ANCA-11; Cognoptix, Acton, MAunder license from the University of California SanDiego; Fig. 6) is the lead from a family of fluo-rescent A� binding compounds administered as anophthalmic ointment prior to measurement of A� inthe lens of the eye using a proprietary Fluorescent Lig-and Scanning device (the SAPPHIRE II system) forthe potential diagnosis of AD. By December 2012, theSAPPHIRE II drug/device technology was in clinicaltrials in the US. In September 2013, data from a pre-pivotal multicenter trial were reported. By detection ofa specific fluorescent signature of ligand-marked A�in the supranucleus region of the lens, SAPPHIRE IIwas able to differentiate 20 patients clinically diag-nosed with probable AD from 20 age-matched healthysubjects with a sensitivity of 85% and a specificity of95%. The data validated results obtained in a previousproof-of-concept trial of the drug/device combinationeye test. The SAPPHIRE II results correlated well withdata obtained by PET A� brain imaging (ThomsonReuters Pharma, update of June 9, 2014).

18F-FDDNP (University of California Los Angeles(UCLA) and Siemens Medical Solutions Molecu-lar Imaging, Knoxville, TN; Fig. 6) was the firstPET tracer used in vivo for detection of cere-bral A� plaques in 2002 [590]. 18F-FDDNP is asensitive in vivo PET imaging probe to map andquantify the dynamic regional localization of tau fib-rillar aggregates in progressive supranuclear palsy(PSP) [591]. UCLA clinicians evaluate 18F-FDDNPfor the potential PET imaging of chronic traumatic


Fig. 6. PET ligands for amyloid-�.

encephalopathy. In March 2013, an open-label, sin-gle group assignment, Phase II study was initiated inhealthy volunteers (expected n = 50) at risk for chronictraumatic encephalopathy in the US (Thomson ReutersPharma, update of January 3, 2014).

123I-ABC-577 (Nihon Medi-Physics, Tokyo) isdeveloping a radioiodinated imidazopyridine deriva-tive A� imaging agent for the potential use in thediagnosis of AD. By July 2014 clinical studies hadbegun (Thomson Reuters Pharma, update of July 17,2014). The structure was not communicated.

BAY-1006578 (Piramal Imaging following an assetacquisition from Bayer) was in Phase I clinical trials inFinland and Sweden since June 2010 (n = 36). By Octo-ber 2011 the trial was completed (Thomson ReutersPharma, update of August 9, 2013). The structure wasnot communicated. A potential follow up compound isBAY-1008472 (Fig. 6) [592].

123I-DRM-106 (Fujifilm RI Pharma, Tokyo, Fig. 6)is a SPECT ligand for potential use in imaging of A� inthe diagnosis of AD. 125I-DRM-106 showed excellentbrain permeability and metabolic stability in rats, withan in vitro IC50 value of 1.86 nM. In ex vivo samplesfrom Tg2576 mice, 125I-DRM-106 was more sensi-

tive in detecting A� plaque deposits than 125I-IMPYand, in a post mortem human brain, the agent detectedA� plaque-associated radioactivity in the hippocam-pus of an AD patient. In vivo imaging in transgenicmice showed the agent to have an excellent corre-lation with 11C-PiB in detecting A� plaque deposits(Thomson Reuters Pharma, update of July 23, 2014).

18F-FC-119S (Korea Institute of Radiological andMedical Sciences, KIRAMS, Seoul, Fig. 6) is a PETtracer to image A� deposition for the diagnosis of ADin Phase I clinical studies (Thomson Reuters Pharma,update of September 4, 2013).

18F-Flubatine (Helmholtz Zentrum DresdenRossendorf and Ascenion, Munich; Fig. 6) is apotential PET imaging agent for the diagnosis ofAD in Phase I clinical trials since November 2012in Germany (Thomson Reuters Pharma, update ofOctober 25, 2013).

18F-FPYBF-1 (Fig. 6) and 18F-FPYBF-2 (KyotoUniversity) are pyridyl benzofuran derivatives as PETtracers for the potential use in imaging of A� plaques.A Phase I clinical trial was initiated in March 2013 inJapan [593] (Thomson Reuters Pharma, update of June9, 2014).


123I-MNI-672 (Molecular NeuroImaging, NewHaven, CT) is a single-photon emission computedtomography imaging agent of A� for the potentialdiagnosis of AD patients. In April 2013, an exploratory,open-label, non-randomized, safety/efficacy, Phase Istudy was initiated in patients (expected n = 6) withAD in the US (Thomson Reuters Pharma, update ofMay 30, 2013). The structure was not communicated.

18F-BF-227 (Fig. 6) is a valuable radioligand forimaging dense A� plaques [594].

DWJ-303 (Daewoong Pharmaceuticals, Seongnam,South Korea) is an imaging agent for the potential diag-nosis of AD (Thomson Reuters Pharma, update of May21, 2014).

18F-Hexethal (Pfizer, under license from the Uni-versity of Aberdeen), a barbiturate derivative, is anA� imaging agent [595] (Thomson Reuters Pharma,update of March 22, 2013).

Pronucleon peptide (Adlyfe, Rockville, MD andQPS Austria Neuropharmacology, Grambach) is basedon the human A� sequence 16 to 35, with pyrene dibu-tyrate moieties attached to the N and C-termini. Thispeptide exhibits a shift in fluorescence emission frompyrene excimer to pyrene monomer emission result-ing from a conformational change. Administered totransgenic mice either intranasally or intravenously thepeptide can localize to the brain and labels plaquesthroughout the brain [596–598].

18F-labeled 2-phenylindole derivatives were eval-uated as PET imaging probes for A� plaques[599]. Novel cyclopentadienyl tricarbonyl complexesof 99mTechnetium mimicking chalcone were pre-sented as potential single-photon emission computedtomography imaging probes for A� plaques [600].18F-curcumin derivatives were evaluated for A�plaque imaging [601]. Curcumin analogues were syn-thesized for in vivo fluorescence imaging of A�[602]. Radioiodinated benzyloxybenzene derivativesare evaluated to target amyloid-� plaques [909].

13N-labelled azo compounds were investigated forA� imaging in mice [603].

The development of 11C-AZD-2184 and 11C-AZD-2995 (AstraZeneca; [604–609]), 18F-Florbetapir dimer (for the potential diagnosis of cerebralamyloid angiopathy (CAA), Avid Radiopharmaceuti-cals; [610]) and of 123I-MNI-168, 123I-MNI-308,and 18F-MNI-558 (Molecular NeuroImaging) wasterminated.

Inhibitor of serum amyloid P component binding

No new development.

Vaccines against amyloid-β

Affitope AD-02 (Affiris, Vienna, AT and licenseeGlaxoSmithKline Biologicals) is a six amino acid pep-tide vaccine targeting the N-terminus of A� only,when it is free. The adjuvant is aluminum hydrox-ide. The antibody response is focused exclusively onA� and did not show crossreactivity to A�PP [611,612]. A European Phase II clinical trial in 420 patientsstarted in April 2010. Proof-of-concept data werecommunicated on June 4, 2014. A statistically signifi-cant correlation with biomarker hippocampus volumewas not seen within the observation period of 18months (Thomson Reuters Pharma, update of June 11,2014).

CAD-106 (presumed to be amilomotide, CytosBiotechnology, Zurich and Novartis, Basel) is an A�1-6peptide linked to a Q� virus-like particle for thes.c. treatment of patients with AD. In March 2010a randomized, placebo-controlled, multicenter, PhaseII trial began in patients (n = 120) in the US, Canadaand Europe with mild AD (Thomson Reuters Pharma,update of May 23, 2014).

ACI-24 (AC Immune, Lausanne, Switzerland) iscurrently evaluated in a Phase I/II clinical trial in Den-mark, Finland and Sweden (Thomson Reuters Pharma,update of March 24, 2014).

Affitope-AD-03 (MV-01, MimoVax; Affiris,Vienna, AT and licensee GlaxoSmithKline Bio-logicals), an AFFITOPE-based vaccine targetingtruncated and modified forms of A�, entered a PhaseI clinical trial in October 2010 in Austria (ThomsonReuters Pharma, update of April 29, 2014).

There are numerous vaccine preparations in preclin-ical evaluation (in alphabetical order):

3A Peptide, a random peptide oligomer, was usedto vaccinate 3xTg AD mice. 3A peptide reducedtotal plaque load (A� burden) and improved cog-nitive function in the 3xTg AD mouse brains ascompared to controls. Vaccination with this nonhumanamyloid oligomer generated high titers of antibodiesspecifically recognizing A� oligomers, which in turninhibited accumulation of A� pathology in mice. Therewas a significant decline in the level of hyperphospho-rylated tau [613].

AD-2203 (BAN-2203; BioArctic Neuroscience,Stockholm) is an immunotherapeutic vaccine target-ing A� protofibrils (Thomson Reuters Pharma, updateof January 21, 2014).

ADepVac (Ichor Medical Systems, San Diego, CAin collaboration with the University of CaliforniaIrvine and the Institute for Molecular Medicine, IMM,


South Laguna, CA) is a DNA vaccine using the Tri-Grid electroporation technology [614]. Translationalstudies in macaques were published [615]. Additionalpapers were disclosed [616–619] (Thomson ReutersPharma, update of March 3, 2014).

AFFITOPE AD-0X (Affiris, Vienna, Austria) is apeptide-based vaccine that targets A� and modifiedA� peptides for the potential s.c. treatment of AD(Thomson Reuters Pharma, update of November 25,2013).

ALZ-101, ALZ-102, and ALZ-103 (Alzinova, aspin-off of MIVAC Development, both Goteborg, Swe-den) are specific oligomer-directed peptide vaccines,which acted as mimetics of natural A�42 oligomers(Thomson Reuters Pharma, updates of November27, 2013, of June 19, 2013 and of June 20, 2013,respectively).

BS-1 BACE inhibitor mAb vaccine (NasVax,Ness-Ziona, Israel under license from Ramot at TelAviv University) is based on a lead mAb candidateblocking �-site-1, which inhibited the ability of BACEto cleave A�PP (Thomson Reuters Pharma, update ofJanuary 22, 2014).

Lu AF20513 (Lundbeck, Valby, DK in collabo-ration with Otsuka, Tokyo) is a novel AD epitopevaccine, in which the T-helper (Th) cell epitopes ofA�42 were replaced by two foreign Th epitopes fromtetanus toxoid (TT), P2 and P30, and the immunodom-inant B-cell epitope of A�1-42. Lu AF20513 inducedrobust non-self T-cell responses and the production ofanti-A� antibodies that reduced AD-like pathology inthe brains of Tg2576 mice without inducing microglialactivation [620] (Thomson Reuters Pharma, update ofMay 15, 2014).

MER-5101 (Mercia Pharma, New York, NY) is avaccine comprised of an A� peptide conjugate coupledto an immunogenic carrier protein and the company’sTh2-biased adjuvant MAS-1. The vaccine generated arobust anti-A� antibody response and attenuated A�pathology and cognitive deficits in APPSWE/PS1�E9transgenic mice [621] (Thomson Reuters Pharma,update of April 29, 2013).

Polypeptide vaccine (Zhejiang Xianju Pharmaceu-tical, Zheijang, China) is evaluated for the potentialprevention and treatment of AD (Thomson ReutersPharma, update of July 11, 2013).

Proteasome-based vaccine V-2 intranasal (GSK)is investigated by for the potential treatment of AD(Thomson Reuters Pharma, update of June 5, 2013).

RGD-DiTox [382–401]-KK-ABeta [1–13] (Dai-ichi Sankyo, Tokyo) is a novel A� peptide vaccine,which significantly increased cognitive performance

in mice (Thomson Reuters Pharma, update of July 15,2014).

University of California San Diego scientists areinvestigating an A� anti-ideotype vaccine developedusing a polypeptide based targeting molecule thatshows great selectivity for AD plaques (ThomsonReuters Pharma, update of July 11, 2013).

Excellent papers on A� vaccines from universi-ties were presented (in chronological order): 2012:non-human random sequence amyloid oligomer mimic[622], a new gene vaccine encoding ten repeats ofA�3-10 [623], active DNA Abeta42 vaccination [624],short A� immunogens [625], mutated A� sensitizeddendritic cells [626], preventive immunization [627]2013: immunotherapeutic efficiency of a tetravalentA�1-15 vaccine [628], recombinant DNA vaccine[629], multivalent A�3-10 DNA vaccine [630], a pep-tide prime-DNA boost immunization [631], a newDNA vaccine YM-3711 [632], an effective DNA epi-tope chimeric vaccine [633], 2014: vaccination, whichinduced changes in pro-inflammatory cytokine levelsand lead to cognitive improvement [634] and recom-binant chimeric vaccines [635]. The novel vaccinepeptide GV1001 effectively blocked A� toxicity [636].

Excellent reviews on A� vaccines have been pro-vided (in chronological order) 2012: [637], 2013: [638,639], 2014: [640, 641].

The development of EB-101 (Atlas Pharmaceu-ticals), NU-700 (Nuron Biotech), V-950 (Merck;[642, 643]) and vanutide cridificar (ACC-001,PF-05236806; Janssen Alzheimer Immunotherapyacquiring Elan’s Alzheimer’s Immunotherapy Pro-gram and Pfizer; [642, 644]) was terminated.

Antibodies against amyloid-β

Solanezumab (LY-20622430; Lilly) is a mid-domain humanized monoclonal antibody selective forsoluble A�. Solanezumab failed to meet the cogni-tive and functional primary endpoints of two Phase IIIAD trials, but showed a significant reduction in cog-nitive decline in patients with mild AD [645, 646].In July 2013 a randomized, double-blind, parallel-group, Phase III trial (Expedition 3) was initiated tocompare the effect of solanezumab in slowing the cog-nitive and functional decline of AD versus placeboin patients with mild AD (expected n = 2100) in theUS, Europe, Canada and Australia (Thomson ReutersPharma, update of May 20, 2014).

The National Institute on Aging (Bethesda, MD)announced funding of a three-year AD prevention trial,which will enroll 1’000 patients of age 70–85 years,


who have evidence of the abnormal A� protein build-ing up in the brain detected by PET scans. For a review,see [647].

Gantenerumab (R-1450, RG-1450; Roche, Baselin collaboration with its Japanese subsidiary Chugai,Tokyo under license from MorphoSys, Martinsried,Germany) is a human anti-A� monoclonal antibody.By January 2011 a Phase II trial in patients with prodro-mal AD had been initiated. In June 2012 the trial wasexpanded to a phase II/III trial from 360 to 770 partic-ipants in the US, Canada, EU, Mexico and Argentina.A Phase III study in mild AD patients was expected tostart in May 2014 (Thomson Reuters Pharma, updateof May 27, 2014).

BAN-2401 (Eisai, Tokyo under license from Bioarc-tic Neuroscience, Stockholm, Sweden) is a humanizedversion of the mouse monoclonal antibody mAb158that targets the large soluble amyloid product (LSAP;protofibril A� [PFA�]). Eisai started Phase II trials inDecember 2012 in the US and in February 2013 inEurope (Thomson Reuters Pharma, update of May 14,2014).

Crenezumab (MABT-5102A; RG-7412; Genen-tech, South San Francisco, CA, Roche Holding underlicense from AC Immune, Lausanne, Switzerland)is an anti-A� humanized monoclonal antibody as aconformation-specific, passive immunotherapy for thepotential i.v or s.c. treatment of AD [648]. A PhaseII clinical trial (n = 372) was initiated in April 2011in the US, Canada and Europe. In December 2013 aPhase II trial began in PSEN1 E280A mutation car-riers in Colombia in a preclinical stage of AD. Atthe Annual Meeting of the Alzheimer’s Association inCopenhagen, July 12–17, 2014 results from a PhaseII study in 431 mild to moderate Alzheimer’s dis-ease patients were presented. Mild Alzheimer patientsshowed 35.4% reduction of cognitive decline and a19.6% reduction of global functional decline, both sta-tistically significant, after treatment for 18 months,whereas moderate Alzheimer patients did not. This isreminiscent of the results with solanezumab of 2013,where also mild Alzheimer patients only responded toantibody treatment (Thomson Reuters Pharma, updateof July 18, 2014).

GSK-933776A (GSK) is a monoclonal antibody forthe i.v. treatment of AD and age-related macular degen-eration. A Phase II age-related macular degenerationtrial (n = 162) started in the US in August 2011. Dataon the Phase I study were published [649] (ThomsonReuters Pharma, update of April 17, 2014).

The human polyclonal IgG antibody preparationknown as Intravenous Immunoglobulin (IVIG)

has been under study as a potential treatment forAD since 2002 [650]. The brain bioavailability ofhuman intravenous immunoglobulin and its trans-port through the murine blood-brain barrier wasinvestigated [651]. Low-dose human IVIG treatmentimproved synaptic plasticity and cognitive functionthrough C5a-mediated induction of the CREB/CEBPpathway, while the levels of A� in the brain were notsignificantly affected [652]. IVIG treatment protected3xTg AD mice from memory deficit and A� pathology[653]. IVIG treatment exerted antioxidant and neurop-reservatory effects in preclinical models of AD [910].The mechanistic effects of IVIG in neuroinflammatorydiseases were described [911]. A� concentration andstructure influenced the transport and immunomodu-latory effects of IVIG [654]. Longitudinal effects ofIVIG on the AD cerebrospinal fluid proteome weredescribed [655]. IVIG is beneficial in the therapy ofAD by inducing efflux of A� from the brain throughthe low-density lipoprotein receptor-related protein-1(LRP1) in the blood-CSF barrier (BCB) [912].

Octagam (Octapharma, Lachen, Switzerland) isa 10% liquid intravenous immunoglobulin launchedfor the treatment of primary immunodeficiency. Theresults of the first Phase II study in AD patients was pre-sented in Lancet Neurology [656]. A second Phase IItrial was initiated in Germany in January 2013 (Thom-son Reuters Pharma, update of July 16, 2014).

Privigen (CSL Behring, King of Prussia, PA)is a launched 10% liquid intravenous immunoglob-ulin stabilized with proline for the treatment ofprimary immunodeficiency and possibly AD. Intra-venous immunoglobulin shifted microglial activationstate toward anti-inflammatory activity and reversedA�–mediated LTP inhibition (Thomson ReutersPharma, update of September 19, 2013).

Ponezumab (PF-04360365, RN-1219; Pfizer) is ahumanized IgG2 monoclonal antibody specific againstthe C-terminus of A�40 in preclinical evaluation for thepotential treatment of CAA. In April 2013, a Phase IICAA trial was initiated. Preclinical and Phase I datawere published [657–660] (Thomson Reuters Pharma,update of May 16, 2014).

Aducanumab (NI-101, BIIB-037, BART; BiogenIdec, Weston, MA under license from NeuroimmuneTherapeutics, Zurich, Switzerland) is a recombinantchimeric human IgG1 mAb targeted against A�. APhase I clinical trial (n = 40) in patients with mild tomoderate AD started in the US in July 2011 (ThomsonReuters Pharma, update of June 13, 2014).

BI-1034020 (Boehringer Ingelheim user licensefrom Ablynx, Gent, Belgium) is a nanobody therapeu-


tic, a naturally-occurring single chain antibody derivedfrom Camelidae. Epitope structure and binding affinityof single chain llama anti-A� antibodies were stud-ied by proteolytic excision affinity-mass spectrometry[661]. In October 2013 a Phase I single-center, par-tially randomized, single-blind, placebo-controlled,safety, tolerability, pharmacokinetic and pharmacody-namic study of single ascending doses of i.v. and s.c.nanobody was initiated in healthy volunteers (expectedn = 80) in Germany (Thomson Reuters Pharma, updateof May 23, 2014).

LY-3002813 (Eli Lilly, Indianapolis, IN) is anantibody targeted against the N-terminal truncatedpyroglutamate-3 isoform of A� for the potential s.c. ori.v. treatment of AD. A Phase I clinical trial in patients(expected n = 100) with MCI due to AD or mild tomoderate AD was initiated in the US and Japan inMay 2013. The antibody cleared A� plaques in ADmice without causing microhemorrhage [662] (Thom-son Reuters Pharma, update of April 25, 2014).

MEDI-1814 (AstraZeneca) is a monoclonal anti-body for the potential treatment of AD via i.v. or s.c.formulations. In January 2014, a randomized, double-blind, placebo-controlled, parallel-assigned, Phase Itrial was planned to be initiated in the US in elderly sub-jects (expected n = 121) with AD to evaluate the safety,tolerability, pharmacokinetics and pharmacodynam-ics of single and multiple ascending doses (ThomsonReuters Pharma, update of March 7, 2014).

NEOD-001 (Onclave Therapeutics, Dublin, awholly owned subsidiary of Prothena, formerlyNeotope Biosciences following Prothena’s demergerfrom Elan) is a therapeutic humanized IgG1 kappamonoclonal antibody against serum amyloid A and ALamyloid, for the potential i.v. treatment of systemicamyloidosis, including AL amyloidosis (light-chainamyloidosis; primary amyloidosis) and AA amyloi-dosis (secondary amyloidosis) in Phase I clinical trialssince April 2013 in the US. In February 2012 the drugwas awarded Orphan status by the FDA for AA amyloi-dosis and AL amyloidosis (Thomson Reuters Pharma,update of May 7, 2014).

There are currently many antibodies for the poten-tial treatment of AD and closely related diseases inpreclinical evaluation (in alphabetical order):

1E8 (CSIRO Preventive Health Flagship, Parkville,AUS) is anti-A� monoclonal antibody targetingresidues 17-22 of A�, of which the single chain anti-body fragment (scFv) derivative was generated. Thesoluble 1E8 scFv bound to the central region of A�with an affinity of 55 nM and significantly reducedfibril formation of A� [663].

9D5 antibody (University of Gottingen/MBM Sci-enceBridge) targets pyro-Glu-A� peptide oligomersfor the potential diagnosis and treatment of AD (Thom-son Reuters Pharma, update of July 8, 2014).

A-887755 (ABT-736; AbbVie, North Chicago, IL,a spin-out of Abbott Laboratories) is an A�, oligomer-selective, mouse monoclonal antibody. The humanizedmAb version is ABT-736. Both were generated usinga homogenous synthetic A�20-42 oligomer peptide(Thomson Reuters Pharma, update of May 14, 2014).

Aglycosylated ponezumab (Intellect Neuro-sciences, New York, NY) is a IgG2 monoclonalantibody against A� employing its ANTISENILINtechnology (Thomson Reuters Pharma, update ofFebruary 8, 2013).

Aglycosylated murine ponezumab (Pfizer, NewYork, NY) is a IgG2 monoclonal antibody against A�(Thomson Reuters Pharma, update of July 26, 2013).

Antibody therapeutic program (Alector, SanFrancisco, CA in collaboration with Adimab, Lebanon,NH) is developing leads for four major targets for thepotential treatment of AD (Thomson Reuters Pharma,update of November 29, 2013).

Antipyroglutamate-3 amyloid-� mAb (Probio-drug, Halle, Sachsen-Anhalt, Germany) is an IgG1monoclonal antibody for the potential treatment ofAD. The mAb significantly reduced total plaque depo-sition in A�PPswe/PS1dE9 transgenic mice [664].A 500 mg dose of the antibody resulted in improve-ment in acquisition learning in the water T-mazetest in A�PPswe/PS1dE9 transgenic mice. Note thatoligomeric pyroglutamate A� is present in microgliaand a subfraction of vessels in patients with AD,which has implications for immunotherapy [665](Thomson Reuters Pharma, update of December 23,2013).

KHK-6640 (Kyowa Hakko Kirin, Tokyo underlicense from Immunas Pharma, Kanagawa, JP) is anantibody targeting amyloid-� oligomers (A�Os) forthe potential treatment of AD. In June 2014 a ClinicalTrial Application (CTA) was accepted by the Belgianregulatory authority to initiate a Phase I trial in Europe(Thomson Reuters Pharma, update of June 19, 2014).

Monoclonal antibodies (State University of NewYork at Stony Brook) are directed against the amyloidbinding domain of myelin basic protein for the poten-tial treatment of AD [666] (Thomson Reuters Pharma,update of December 6, 2013).

Oligomeric amyloid-� monoclonal antibodies(Immunome, Wynnewood, PA) were created using thenative human monoclonal antibody (N-huMAB) tech-nology in-licensed from MIT (Cambridge, MA) and


Thomas Jefferson University (Philadelphia, PA) for thepotential treatment of AD (Thomson Reuters Pharma,update of November 28, 2013).

Oligomer-specific i-bodies (Crossbeta Bio-sciences, Utrecht, the Netherlands and AdAlta,Victoria, AUS) are humanized analogues of shark anti-bodies for the potential treatment and diagnostic use inAD. They are made using AdAlta’s i-body technologyand Crossbeta’s stabilized A� oligomers (ThomsonReuters Pharma, update of December 20, 2013).

scFv-h3D6 (Universitat Autonoma de Barcelona) isa recombinant single-chain variable antibody fragmentand a derivative of bapineuzumab [667–670] (Thom-son Reuters Pharma, update of October 28, 2013).

Single-chain camelide antibody fragments(CNRS/FIST) are A�1-42 and phosphorylcholinemodulators for the potential treatment and diag-nosis of neurodegenerative diseases including AD(Thomson Reuters Pharma, update of April 22, 2014).

Excellent papers on A� antibodies from universitieswere presented: 2012: [671–673], 2013: [674–680].

Excellent reviews were provided 2012: [681], 2013:[682–689], 2014: [690–695].

The development of 4E10 (a monoclonal anti-body targeting a proprietary pathological A� targetepitope, Prana Biotechnology), 6F6 (an anti-A� mon-oclonal antibody, GSK), amyloid precursor proteinC-terminal fragment-targeted monoclonal anti-bodies (Ecole Polytechnique Federal de Lausanne),A� deposition-inhibiting antibodies (amyloidosis,Kinexis), immune globulin intravenous human(Baxter International; [642, 696–700]), ponezumab(PF-04360365; RN-1219; RI-1219; a humanized mon-oclonal antibody specific for the C-terminus of A�40,Rinat Neuroscience and Pfizer; but a Phase II trial forthe treatment of CAA continues; Thomson ReutersPharma, update of February 20, 2014) and of RN-6G (Rinat Neuroscience, now Pfizer; [701]) wasterminated.

DRUGS INTERACTING WITH TAU, PRION,�-SYNUCLEIN, APOE, AND TDP-43

A hallmark of the AD brain is the presenceof inclusions within neurons that are comprised offibrils formed from hyperphosphorylated microtubule-stabilizing protein tau (paired helical filaments) andneurofibrillary tangles [702, 703]. The mechanismsand targets of tau-induced neurodegeneration were dis-cussed [704]. New perspectives on the role of tau inAD were presented [705]. Extracellular monomeric

tau protein is sufficient to initiate the spread of tauprotein pathology [706]. Sources of extracellular tauand its signaling were described [707]. The prion-likeproperties of tau were described [913]. Phosphoryla-tion of tau protein at sites Ser396 and Ser404 is oneof the earliest events in AD and Down’s syndrome[709]. Mechanistic studies to elucidate the mecha-nism of tau aggregation were disclosed [710]. Thereis a growing consensus that sarkosyl-insoluble taucorrelates with the pathological features of tauopathy[711]. Tau oligomers and fibrils induce activation ofmicroglial cells causing neuroinflammation [712]. Forthe role of tau protein phosphatases, see the review[713]. The �2-adrenergic receptor, protein kinase Aand c-jun N-terminal kinase signaling pathways wereidentified to mediate tau pathology [714]. The func-tional interrelationships of the glutamate system, A�peptides and tau protein were reviewed [715, 716]. Itcould be shown that mTOR regulates tau phosphoryla-tion and degradation [717]. The synaptic accumulationof hyperphosphorylated tau oligomers is associatedwith dysfunction of the ubiquitin-proteasome system[718]. An overview on the ubiquitin-proteasome sys-tem versus the autophagy-lysosome system in thedegradation of tau was published [719]. Intraneuronaltau aggregation precedes diffuse plaque deposition,but A� changes occur before increases of tau incerebrospinal fluid [720]. Therapeutic strategies fortau mediated neurodegeneration were outlined [721].For a novel trans-synaptic mechanism for tau proteintransfer, see [722]. Tau promotes neurodegenerationthrough global chromatin relaxation [723]. For a com-ment, see [724]. Tau also has a critical physiologicalfunction in long-term depression in the hippocampus[725].

Drugs preventing tau, prion or α-synucleinaggregation

LMT-X (TRx-0237, TauRx Therapeutics, Singa-pore) is a potential follow-up compound and prodrug ofRember (methylthioninium chloride, methylene blue,whose development was terminated in March 2013).In September 2012, a Phase III study for frontotempo-ral dementia began in 180 subjects for 12 months. InOctober 2012, two global Phase III studies were initi-ated for AD. The first study involves 833 patients withmild to moderate AD over 12 months, while the sec-ond study includes 500 patients with mild AD over 18months. The clinical trials will be conducted in paralleland on a global basis including sites in Australia, Bel-gium, Canada, Finland, Germany, Italy, Russia, Spain,


Netherlands, Singapore, Malaysia, Taiwan, US andUK. For the review on tau-aggregation inhibitor ther-apy by Wischik et al., see [726] (Thomson ReutersPharma, update of May 7, 2014). The structure wasnot communicated.

ARC-100 (TPI-287, NBT-287, abeotaxane; CorticeBiosciences, New York, NY, formerly Archer Bio-sciences under license from Tapestry Pharmaceuticals,Ankeny, IA, formerly NaPro BioTherapeutics) is athird-generation taxane with an ability to readily crossthe blood-brain barrier for the potential i.v. treatmentof taxane-resistant and taxane-naive cancers, pediatricbrain cancer, AD, PSP, and corticobasal degeneration.The drug is in Phase II clinical trials for melanomasince February 2010, for glioblastoma since April2010, for breast cancer since August 2011 and in PhaseI for AD, neurodegenerative diseases and PSP sinceJanuary 2013 in the US (Thomson Reuters Pharma,update of May 12, 2014). The complex structure wascommunicated.

There are many compounds inhibiting tau aggrega-tion in preclinical evaluation (in alphabetical order):

Anle-138b (University of Munich, Fig. 7) stronglyinhibited formation of pathological oligomers in vitroand in vivo for both prion protein and �-synuclein[727]. (Thomson Reuters Pharma, update of July 10,2014).

ASO-12 (Washington University, St. Louis, MO andIsis Pharmaceuticals, Carlsbad, CA) is an antisenseoligonucleotide that selectively decreased endogenoustau expression throughout the entire mouse CNS for thepotential treatment of tau-based neurodegenerative dis-orders including AD [728] (Thomson Reuters Pharma,update of July 16, 2014).

Diaminothiazoles (University of California SantaBarbara) modified tau phosphorylation and improvedthe tauopathy in mouse models [729].

Gold complexes [Au(bpy)Cl2]PF6 (bpy = 2,2’-bipyridine) and [Au(dien)Cl]Cl2 (dien = diethy-lenetriamine) (Renmin University of China, Beijing)inhibited the aggregation of prion neuropeptides [730].

NIPERAMCD-KTB7, a novel bis-imidazopyri-dine, significantly increased protein phosphatase 2Aactivity in the brains of AD rats [731].

Phtalocyanine tetrasulfonate interfered with taufilament formation by targeting the protein into solubleoligomers [732].

Piperazine derivatives inhibited PrP(Sc) propaga-tion in vitro. A lead structure increased the incubationtime of scrapie infected mice [733].

PTI-51-CH3 (ProteoTech, Kirkland, WA) targetstau protein for the potential treatment of PSP (Thom-

son Reuters Pharma, update of May 26, 2014). Thestructure was not communicated.

Synuclere (PD-82; ProteoTech, Kirkland, WA) isan �-synuclein aggregation inhibitor for the potentialtreatment of PD (Thomson Reuters Pharma, update ofJanuary 10, 2014).

T-22 (ConImm, Galveston, TX) is a tau oligomer-specific monoclonal antibody (TOMA), for thepotential treatment of AD [734] (Thomson ReutersPharma, update of January 22, 2014).

TAR DNA-binding protein-43 (TDP-43) asso-ciated NF-kappa B activation (TANA) inhibitors(ImStar Therapeutics, Vancouver, BC) are investigatedfor the potential treatment of neurological diseasesincluding ALS, dementia, AD, and other neurodegen-erative diseases (Thomson Reuters Pharma, update ofApril 22, 2014).

Tau aggregation inhibitors (Exebryl-2; Pro-teoTech, Kirkland, WA) are containing polyhydrox-ylated aromatic rings spaced by a linker region forthe potential treatment of AD (Thomson ReutersPharma, update of May 6, 2014). Structures were notcommunicated.

Tau aggregation inhibitors (University of Penn-sylvania, Philadelphia, PA), brain-penetrant and orallybioavailable, are investigated for the potential treat-ment of neurodegenerative diseases as AD andfrontotemporal dementia (Thomson Reuters Pharma,update of March 24, 2014). Structures were not com-municated.

Tolcapone and Entacapone, both catechol-O-methyltransferase inhibitors, acted as tau-derivedhexapeptide (306)VQIVYK(311) aggregationinhibitors [735]. See also Part 2, Chapter 2.15. Drugsinteracting with Catechol-O-methyltransferase.

Trifluoperazine rescued human dopaminergic cellsfrom wild-type �-synuclein-induced toxicity [736].

NPT-002 (NeuroPhage Pharmaceuticals, Cam-bridge, MA) is a filamentous bacteriophage targetingA� and tau aggregates for the potential treatment of AD(Thomson Reuters Pharma, update of July 15, 2013).

Excellent papers on small molecule inhibitors of tauaggregation were published by researchers at universi-ties: 2012: [737, 738], 2013: [739–741], 2014: [742].

Excellent reviews on tau-focused drug discovery forAD were presented: 2012: [743–745], 2013: [746],2014: [747–751].

The development of BMS-241027 (Bristol-MyersSquibb), NC-11813 (Eli Lilly and Nymirum), NP-111001 derivatives (Noscira), protein phosphatase2A stimulators (Cognosci), PP2A stimulator (Se-015; Ve-015; Velacor Therapeutics), tau aggregation


Fig. 7. A drug inhibiting prion and �-synuclein aggregation and PET ligands for tau.

inhibitors (Catholic University of Leuven), tauphosphorylation inhibitors (ProQinase), tideglusib(Noscira, previously known as Neuropharma) andof TRx-0014 (methylthioninium chloride, methy-lene blue, Rember; TauRx Therapeutics; Fig. 15;[752–754–765]) were terminated.

Ligands interacting with tau and α-synuclein

A review on tau PET radiotracers was published veryrecently [766].

18F-AV-1451 (18F-T807; Avid Radiopharmaceuti-cals, a subsidiary of Eli Lilly, following an acquisitionfrom Siemens Medical Solution Molecular Imaging,Culver City, CA in April 2013; Fig. 7) is a tau-bindingPET tracer for the diagnosis of AD in Phase II clin-ical trials in patients with AD and MCI in the USsince December 2013. Early clinical PET imagingresults were obtained with 18F-AV-1451 (18F-T807)[767, 768]. 18F-AV-1451 (1 �M) showed tau blockingand A� blocking up to 87 and 5%, respectively. InFebruary 2014 a Phase I study was initiated in patientswith tauopathies including AD, PSP, chronic traumaticencephalopathy, and frontotemporal dementia (Thom-son Reuters Pharma, update of June 11, 2014).

11C-PBB3 (National Institute of Radiological Sci-ences, Chiba, Japan; Fig. 7) is a tau-selective, phenyl-pyridinyl-butadienyl-benzothiazole/benzothiazolium

compound and an i.v. PET imaging agent for the poten-tial diagnosis of AD [769, 770]. The radiosynthesis,biodistribution and metabolite analysis was disclosed[914]. By July 2013 a small-scale Phase I clinicaltrial in AD patients (n = 10) was completed (ThomsonReuters Pharma, update of October 4, 2013).

18F-THK-523 (University of Melbourne) is anF18-labeled arylquinoline derivative for the potentialuse in imaging tau deposition in neurofibrillary tan-gles in AD patients. By September 2012 a PhaseI clinical trial was ongoing. In July 2013 clinicaldata were presented [771–774]. For the structure, see[7] (Thomson Reuters Pharma, update of June 4,2014).

AC Immune (Lausanne, Switzerland in collabo-ration with Piramal Imaging, Berlin) is investigatingtau-targeted PET imaging agents for the potential diag-nosis of AD (Thomson Reuters Pharma, update of July18, 2014).

Aminothienopyridazines are evaluated as imagingligands for tau pathology [775].

BF-188 (Tohoku University; Fig. 7) is evaluated forfluorescence multispectral imaging of tau protein fib-rils [776].

Roche is investigating probes for imaging neurofib-rillary tangles for the potential diagnosis of AD. The2-styrylindolium based fluorescent probes were inli-censed from the Technische Universitat Darmstadt


[777] (Thomson Reuters Pharma, update of February25, 2014).

125I-SIL23 (Washington University School ofMedicine, St. Louis, MO; Fig. 7) was the first radi-oligand binding to �-synuclein fibrils in postmortembrains of PD patients as well as in brains of transgenicmouse models of PD [778, 779].

Significant contributions to novel in vivo tauimaging agents were presented by scientists fromthe Tohoku University (Sendai-Shi, Japan), such as11C-THK-951 [780] (for the structure, see [7]), 18F-THK-5105, 18F-THK-5116 and 18F-THK-5117(Fig. 7) [781, 782] (Thomson Reuters Pharma, updateof February 6, 2014).

18F-THK-5351(Tohoku University, Sendai-Shi,Japan) is a tau-imaging PET tracer, for the potentiali.v. diagnosis of AD. In May 2014 a clinical trial wasexpected to begin in June 2014 (Thomson ReutersPharma, update of May 26, 2014). The structure wasnot communicated.

Bis(arylvinyl)-pyrazines, -pyrimidines, and -pyri-dazines were described as imaging agents for tau fibrilsand A� plaques [783], as were trimethine cyanine dyes[784] and fluorescent rhodanine-3-acetic acids [785]and radiopharmaceuticals based on lansoprazole [786].Research towards tau imaging was reviewed [787].

Vaccines against tau and α-synuclein

AADvac1 (Axon Neurosciences, Vienna, AT), arecombinant misfolded truncated tau protein vaccine,attenuated pathology in vivo in a transgenic rat modelof tauopathy. In May 2013 a 3-month, randomized,placebo-controlled, parallel-group, double-blinded,multicenter, Phase I trial began in Austria, which willassess the tolerability and safety in patients with mildto moderate AD (expected n = 30). The trial was toinclude a 3-month open label extension and, at the time,was expected to conclude in March 2015. An 18-monthfollow-up safety study to the trial (NCT02031198;FUNDAMANT) was expected to begin in January2014 (Thomson Reuters Pharma, update of July 23,2014).

ACI-35 (AC Immune, Lausanne, Switzerland) isa liposome-based phospho-tau peptide vaccine devel-oped using the SupraAntigen technology platform forthe potential treatment of AD [788]. In January 2014 arandomized, double-blind, placebo-controlled, Phase Itrial was initiated in patients with mild to moderate ADto evaluate safety, tolerability and immunogenicity ofdifferent doses of ACI-35 (Thomson Reuters Pharma,update of July 25, 2014).

Immunization of P301L mutant mice with a twelveamino acid peptide of the human tau sequence (aa 395-406) together with CFA impeded the progression ofneurofibrillary histopathology [789].

�-synuclein vaccination prevented the accumula-tion of PD-like pathologic inclusions in a rat model[790]. The immunogenicity of epitope vaccines target-ing different B cell antigenic determinants of human�-synuclein was described [791].

Antibodies against tau, superoxide dismutase 1,α-synuclein, and ApoE

PRX-002 (formerly NEOD-002; Prothena, Dublin,Ireland, formerly Neotope Biosciences followingProthena’s demerger from Elan, and Roche) is an �-synuclein-targeted therapeutic monoclonal antibodyfor the potential i.v. treatment of PD and other synucle-inopathies. In March 2014 a Phase I study was initiatedin the US (Thomson Reuters Pharma, update of May7, 2014).

Anti-oligomeric monoclonal antibodies improvedcognitive function by reducing A� deposition and taupathology in 3xTg-AD mice [792].

Anti-tau antibodies (Bristol-Myers Squibb andUniversity of Pennsylvania, Philadelphia, PA) showeda significant improvement in an object recognitiontest in Tg4510 mice following systemic administra-tion for one month (Thomson Reuters Pharma, updateof December 26, 2013).

AT8 (Washington University School of Medicine,St. Louis, MO) reduced somatodendritic tau load, p-tauimmunoreactivity and silver stained positive neuronswithout affecting A� pathology in 3xTg-AD mice[915].

HJ8.5, HJ9.3, and HJ9.4 (Washington Univer-sity School of Medicine, St. Louis, MO) are humantau monoclonal antibodies that blocked tau aggregateseeding in vitro, markedly decreased tau pathology andimproved cognition in vivo in P301S transgenic mice[793].

Humanized anti-tau monoclonal antibodies (ACImmune, Lausanne, Switzerland) had high specificaffinity binding to pTau. One antibody was outlicensedto Genentech (Thomson Reuters Pharma, update ofJuly 18, 2014).

IPN-007 and IPN-002 (iPierian, South San Fran-cisco, CA, a subsidiary of Bristol-Myers Squibb) aremonoclonal antibodies and tau protein modulators forthe potential treatment of AD, frontotemporal demen-tia and PSP (Thomson Reuters Pharma, update of April30, 2014).


MN-423 (Axon Neurosciences, Vienna, Austria) is ahumanized anti-tau monoclonal antibody for the poten-tial treatment of AD and related neurodegenerativetauopathies. By December 1998 the antibody had beendiscovered. In July 2014 the antibody was humanized(Thomson Reuters Pharma, update of July 23, 2014).

A rabbit monoclonal antibody site-specific fortau O-GlcNAcylated at serine 400 was disclosed byscientists from EMD Serono [794].

SOD1-targeting antibody (PREVENT-ALS;Amorfix Life Sciences, Mississauga, Ontario) is eval-uated for the potential treatment of ALS (ThomsonReuters Pharma, update of July 17, 2014).

A tau oligomer-specific antibody was presented bythe team of Professor Kayed at the University of TexasMedical branch at Galveston for the potential treatmentof neurodegenerative tauopathies including TBI [734,795] (Thomson Reuters Pharma, update of November25, 2013).

Tau-targeted antibody therapy (Prothena, for-merly Neotope Biosciences, Dublin, Ireland, previ-ously a subsidiary of Elan, South San Francisco,CA) is a monoclonal antibody targeted to tau(Thomson Reuters Pharma, update of June 18,2013).

Teijin Pharma (Tokyo) is investigating a programof mAbs targeting against phosphorylated tau proteinfor the potential treatment of AD (Thomson ReutersPharma, update of March 21, 2014).

TNT-Ab (Panorama Research, Sunnyvale, CA) is atau N-terminal antibody delivered through AAV-genetherapy for the potential treatment of neurodegener-ative diseases (Thomson Reuters Pharma, update ofMarch 15, 2014).

TOC-1 (Intellect Neurosciences, New York underlicense from Northwestern University, Evanston,IL) is a tau-oligomer-targeting monoclonal antibody[916–918]. It proved to ber a valuable tool for assess-ing disease progression in the rTg4510 mouse modelof tauopathy [919] (Thomson Reuters Pharma, updateof November 15, 2013).

University of Iowa scientists are investigatingphosphorylated tau targeted monoclonal antibodies,the clone 9G3 targeting tyrosine-18 phosphorylatedhuman tau protein for the potential treatment of AD(Thomson Reuters Pharma, update of August 2, 2013).

VHH-TauA2 (Hoffmann-La Roche, Basel, Switzer-land) is an anti-tau camel single-domain antibody andtau kinase inhibitor for the diagnosis of AD. VHH-R3VQ is an anti-amyloid-� camel single-domainantibody investigated as a diagnostic agent (ThomsonReuters Pharma, update of July 25, 2014).

Several monoclonal anti-apoE antibodies were elu-cidated [796], see also [797].

Excellent papers on passive immunization tar-geting pathological phospho-tau protein were pub-lished: 2012: [798], 2013: [799–802], 2014: [803].Also approaches for the immunotherapy for �-synucleinopathies were discussed [804, 805].

STEM CELLS

Substantial progress was achieved in research ofstem cells for the potential treatment of AD in 2012:[806–809], 2013: [810–815] and 2014: [816–819].

Medial ganglionic eminence-like cells derived fromhuman embryonic stem cells corrected learning andmemory deficits [820]. Embryonic stem cell-basedmodeling of tau pathology was described [821].

Induced pluripotent stem cells may be useful toolsfor disease modeling and drug discovery in AD [822]or neurodegenerative diseases [823, 824]. For a 3D ADculture model in induced pluripotent stem cell-derivedneurons, see [825].

Placenta-derived mesenchymal stem cellsimproved memory dysfunction in an A�1-42 infusedmouse model of AD [826]. Mesenchymal stemcells increased hippocampal neurogenesis [827],enhanced autophagy and increased A� clearance inAD disease models [828]. Intracerebral transplan-tation of adipose-derived mesenchymal stem cellsameliorated neuropathological deficits in AD mice[829]. Bone marrow-derived mesenchymal stem cellscontributed to the reduction of A� deposits [830]and improved memory in rat models of AD [831].Systemic transplantation of human umbilical cordderived mesenchymal stem cells improved impairedcognition in A�PPSWE/PS1dE9 transgenic mice[832].

Neural stem cell transplantation improved spatiallearning and memory via neuronal regeneration inA�PP/PS1/tau triple transgenic mice [833]. Neuralstem cell therapy improved memory in a mouse modelof AD [834].

Mesenchymal bone marrow-derived stem celltherapy (Stemedica Cell Technologies, San Diego,CA) is being developed for the intravenous treatmentof ischemic stroke in Phase I/II since February 2011 inthe US (n = 35). The study was completed in Febru-ary 2013. In February 2014, a Phase III trial forthe treatment of myocardial infarction was initiatedin Kazakhstan (Thomson Reuters Pharma, update ofFebruary 24, 2014).


Autologous fat-derived stem cell therapy (RNL-Astrostem; K-STEMCELL, previously RNL Bio,Seoul) is evaluated for the treatment of cerebral palsy.A Phase II trial was initiated for the treatment of facialhemiatrophy in South Korea in June 2013 (ThomsonReuters Pharma, update of August 20, 2013).

Bone marrow-derived neurotrophic factor-producing mesenchymal stem cells (NurOwn,MSC-NTF; BrainStorm Cell Therapeutics, New York,NY) are adult mesenchymal stem cells secretingneurotrophic factors (GDNF and BDNF) investigatedas a potential treatment of PD, sciatica, and MS. APhase I/II clinical trial in ALS patients started in June2011 in Israel. The trial was fast-tracked by the IsraeliMinistry of Health to a Phase IIa dose-escalating trial,which was initiated in December 2012 (ThomsonReuters Pharma, update of February 26, 2014).

NGN-9076 (Neural stem cell therapy, NeuroGener-ation, Los Angeles, CA) is in a Phase II clinical trial inthe US since May 2007 for the potential treatment ofPD (Thomson Reuters Pharma, update of January 13,2014).

NSI-566RSC (NSI-566; Neuralstem, Rockville,MD) are human neural stem cells (hNSCs) includingspinal cord stem cells for the potential injectable treat-ment of ALS, stroke, HD, and AD. NSI-566 entereda Phase II ALS trial in September 2013 in the US. Inrecent papers, it was demonstrated that transplantationof fetal-derived human neural stem cells improved cog-nitive deficits in rats as was assessed by two separatecognitive tasks [835–837] (Thomson Reuters Pharma,update of May 29, 2014).

Purified human neural stem cell therapy(HuCNS-SC; StemCells, Palo Alto, CA, formerlyCytoTherapeutics under license from NeuroSperes,Calgary, Alberta) is a proprietary transplantable humanneural stem cell therapy for the potential treatment ofspinal cord injury, age-related macular degenerationand AD. Human neural stem cells induced functionalmyelination in mice [838] and in the human brain[839]. Phase II clinical trials for spinal cord injurywere initiated in the US and Canada in December 2011and in Europe in May 2012. StemCells announced inSeptember 2013 dosing of the first high-dose patientin a Phase I/II clinical trial in dry age-related macu-lar degeneration in the US (Thomson Reuters Pharma,update of May 30, 2014).

Sargramostim (Immunex, Seattle, WA, nowAmgen, Thousand Oaks, CA) launched in 1991 andnow marketed by Gemzyme (Cambridge, MA) isa yeast-derived recombinant granulocyte-macrophagecolony-stimulation factor, which stimulates prolifer-

ation and differentiation of hematopoietic progenitorcells. In March 2011, a randomized, double-blind,parallel-assigned, pilot, safety/efficacy Phase II trialwas initiated in patients (expected n = 40) with AD inthe US (Thomson Reuters Pharma, update of June 13,2014).

ASTOPC-1 (GRNOPC-1; Asterias Biotherapeu-tics, Menlo Park, CA, a subsidiary of BioTime,Alameda, CA, from an asset acquisition from Geron,Menlo Park, CA) is a preparation of oligodendrocyteprecursor cells differentiated from a human embryonicstem cell line that produce neurotrophic factors andremyelinate axons for the potential injectable treatmentof spinal cord injury in Phase I clinical trials since Jan-uary 2013 in the US (Thomson Reuters Pharma, updateof June 13, 2014).

Choroid plexus cell therapy (NeurotrophinCell,NtCell; Living Cell Technologies, Sydney, andOtsuka Pharmaceuticals, Tokyo) is an alginate-microencapsulated porcine choroid plexus cell productfor the potential treatment of neurodegenerative dis-eases including HD and PD and dementia. Choroidplexus implants rescued AD-like pathologies by mod-ulating A� degradation [840]. The preparation is inPhase I clinical trials for the treatment of PD in NewZealand since June 2013 (Thomson Reuters Pharma,update of April 1, 2014).

Neurostem-AD (Medipost, Seoul) is an umbilicalcord blood-derived mesenchymal stem cell therapy,which regenerates nerve cells. A Phase I trial has beeninitiated in February 2011 in patients (expected n = 9)with dementia of Alzheimer-type in South Korea.Multiple low-dose infusions (or intravenous adminis-tration) of human umbilical cord blood cells improvedcognitive impairments and reduced A� associated neu-ropathology in AD mice [841, 842] (Thomson ReutersPharma, update of May 6, 2014).

NGN-9077 (Neural stem cell therapy; NeuroGen-eration, Los Angeles, CA) is in Phase I clinical trialsin the US since May 2007 for the potential treatmentof multiple system atrophy and Shy Drager syndrome(Thomson Reuters Pharma, update of January 15,2014).

There are several stem cell preparations in preclini-cal evaluation (in alphabetical order):

Allopregnanolone (University of Southern Cali-fornia, Los Angeles, CA) is a potent and highlyefficacious proliferative agent in vitro and in vivo ofboth rodent and human neural stem cells [843–846].For recent reviews on allopregnanolone, see [847–849](Thomson Reuters Pharma, update of December 4,2013).


Fig. 8. A stem cell promoter, an amyloid-� fibrinogen interaction inhibitor, and a heat shock factor 1 activator.

Induced multipotent neural stem cell therapy(University of South Australia, Adelaide) are devel-oped by reprogramming mammalian fibroblasts usingundisclosed small molecules for the potential treat-ment of neurodegenerative diseases (Thomson ReutersPharma, update of January 7, 2014).

Marrow-derived multipotent adult progenitorcell therapy (McLean Hospital, Belmont, MA) areengineered to express �-secretase cleaved A�PPfragment (sA�PP�) for the potential i.v. treatmentof neurodegenerative diseases (Thomson ReutersPharma, update of January 10, 2014).

Neural stem cells (University College of London)can differentiate into retinal neurons to aid in the inte-gration of cells into retina for the potential treatmentof eye diseases including glaucoma (Thomson ReutersPharma, update of November 29, 2012).

NGN-9078 (Neural stem cell therapy; NeuroGen-eration, Los Angeles, CA) is in preclinical evaluationfor the potential treatment of thalamic stroke (ThomsonReuters Pharma, update of January 15, 2014).

NGN-9079 (Neural stem cell therapy; NeuroGen-eration, Los Angeles, CA) is in preclinical evaluationfor the potential treatment of AD. Transplantation ofneuronal cells into the brain was shown to improve anddelay the symptoms of AD in animal models (ThomsonReuters Pharma, update of January 13, 2014). Otherneural stem cell therapies are evaluated for the poten-tial treatment of demyelinating diseases and spinalcord injury (Thomson Reuters Pharma, update of Jan-uary 13, 2014) and for brain injury (Thomson ReutersPharma, update of January 15, 2014).

NWL-NSC (neural stem-like cells; New World Lab-oratories, Laval, Quebec) are autologous stem cellsderived from somatic cells using a way of “repro-gramming” without any genetic engineering for thepotential treatment of neurological diseases including

spinal cord injury, TBI, PD, MS, AD, stroke, ischemia,and injury (Thomson Reuters Pharma, update of Jan-uary 28, 2013).

Valproic acid can induce neurogenesis of neuralprogenitor/stem cells both in vitro and in vivo viamultiple signaling pathways [850]. It reduced neuriticplaque formation in A�PPSWE/PS1A246E transgenicmice [851]. It attenuated neuronal loss in the brain ofA�PP/PS1 double transgenic AD mice model [852]and alleviated memory deficits in a transgenic mousemodel of AD [853]. It is a useful mood stabilizer inAD patients.

Xcel-hNu-001 (San Diego Regenerative MedicineInstitute) constitutes human pluripotent embryonicstem cell derived neuronal progenitors and neurons forthe potential treatment of neurological diseases includ-ing motor neuron disease, spinal cord injury, AD, PD,and ALS (Thomson Reuters Pharma, update of July21, 2014).

ZY-1 (Shanghai Jiao Tong University, Fig. 8)is an �4�2 nicotinic acetylcholine receptor ago-nist, which promoted proliferation and migrationof adult hippocampal neural stem/progenitor cells[854, 855].

The development of the brain-derived stem celltherapy (Celprogen in collaboration with the IndianaUniversity School of Medicine) and stem cell differ-entiation inducers (Samaritan) was terminated.

MISCELLANEOUS

A� fibrinogen interaction inhibitor RU-505 (TheRockefeller University, New York, NY; Fig. 8) restoredthe A�-induced altered fibrin clot formation andimproved cognitive impairment in mouse models ofAD [856].


ATF4 (Activating transcription factor 4) inhibitors(Columbia University, New York, NY) are evaluatedfor the potential treatment of AD (Thomson ReutersPharma, update of November 26, 2013). Structureswere not communicated.

Carbamazepine, an autophagy enhancer, alleviatedmemory deficits and cerebral A� pathology in a mousemodel of AD [857].

Complement factor inhibitors (Annexon, PaloAlto, CA) are investigated for the potential treatmentAD (Thomson Reuters Pharma, update of March 8,2013). Structures were not communicated. Annexonalso evaluates fully humanized antibodies againstspecific components of the complement system forthe potential treatment of neurodegenerative diseases(Thomson Reuters Pharma, update of July 24, 2014).

Heat Shock Factor 1 activators (Duke University,Durham, NC; one example in Fig. 8) are investigatedfor the potential treatment of neurodegenerative disor-ders such as AD, PD, and HD [858, 859].

JRP-900 (an autophagy inducer, Prous Institute forBiomedical Research, Barcelona) is investigated forthe potential treatment of neurodegenerative diseaseincluding AD, ALS, HD, and PD (Thomson ReutersPharma, update of January 22, 2014). The structurewas not communicated. For reviews on autophagy inAD and tauopathies, see [719, 860–863], in neurode-generative disorders, see [864].

Klotho modulators (Boston University) are com-pounds, which upregulate the expression of theanti-aging protein Klotho for the potential treatmentof MS, AD, and symptoms of aging including cogni-tive decline [865] (Thomson Reuters Pharma, updateof January 31, 2013). Structures were not communi-cated. Cerebrospinal fluid Klotho concentrations arelower in AD patients [866]. The neuroprotective effectof Klotho is mediated via regulation of members of theredox system [920].

Low-dose therapy Levetiracetam (AgeneBio,Carmel, IN under license from John Hopkins Univer-sity, Baltimore, MD) is investigated for the potentialtreatment of aMCI in Phase II clinical trials sinceDecember 2009 in 144 aMCI patients in the US (forthe structure, see [7]). By November 2013, positivePhase IIa results were reported. At that time the FDAgranted for a pre-IND meeting in the first quarter of2014 for a phase II/III trial. Reduction of hippocam-pal hyperactivity in aMCI patients by using a low doseof levetiracetam improved cognition [867] (ThomsonReuters Pharma, update of June 4, 2014).

miRNA mimetics (University of Göttingen andMBM ScienceBridge GmbH) are investigated for the

potential diagnosis and treatment of memory impair-ment. For a review of the research status of theregulation of miRNA on BACE-1 see [921] (ThomsonReuters Pharma, update of July 8, 2014).

MT-007 (Socratech, Rochester, NY) is a low-density lipoprotein receptor related protein clusterIV mutant (LRPIV) with glycine replacing asparticacid residue 3674. In C57BC/6 mice LRPIV-D3674G(20 mg/kg i.v. for 5 days) reduced A�40/42 in brainto significantly lower levels compared with wild-typeLRPIV (Thomson Reuters Pharma, update of Novem-ber 26, 2013).

MTD-TFAM (Gencia, Charlottesville, VI) is arecombinant human mitochondrial transcription fac-tor A modified with a mitochondrial transductiondomain that transports the product across membranesinto mitochondria for the potential treatment of mito-chondrial diseases, including inherited mitochondrialrespiratory chain disease and neurodegenerative dis-eases such as PD, AD, and ALS (Thomson ReutersPharma, update of March 24, 2014).

Proteostasis modulators (AlzProtect (Loos, Nord-Pas de Calais, France) are investigated for the potentialtreatment of neurological diseases, including HD, PD,ALS, frontotemporal lobar dementia, and AD (Thom-son Reuters Pharma, update of November 6, 2013).

Recombinant TGF-� agonists (Palo Alto Insti-tute for Research and Education, CA) are investigatedfor the potential treatment of AD (Thomson ReutersPharma, update of April 7, 2014). Structures were notcommunicated.

XN-001 (an enhancer of the function of thedihydropyrimidinase-related protein 2, Xonovo,Wilmington, DE in collaboration with the OklahomaMedical Research Foundation, Oklahoma City, OK)is the lead from a program of small molecule syntheticderivatives of lanthionine ketimine for the potentialoral treatment of neurodegenerative diseases includ-ing AD. XN-001 decreased microglial inflammatorycytokines and treated all three hallmarks of AD inexperimental triple transgenic mice by reducing A�peptide burden, reducing phospho-tau, and relievingcognitive decline (Thomson Reuters Pharma, updateof December 26, 2013).

CONCLUSION

No AD medication or cognitive enhancer waslaunched in 2013. FDA approved the A� imaging agent18F-flutemetamol (18F-Vizamyl, GE Healthcare) inOctober 2013. EMA and FDA approved the A� imag-


ing agent 18F-florbetaben (Neuraceq, Piramal) inFebruary and March 2014, respectively.

Currently there are three Phase III AD trials ofdisease modifying drugs underway, of the mono-clonal antibodies against A� solanezumab (Lilly) andgantenerumab (Roche) and of LMT-X (TRx-0237,TauRx Therapeutics), a tau aggregation inhibitor.

There are two Phase III clinical trials of an A�PET imaging agent 18F-NAV-4694 (Navidea) and ofthe vesicular monoamine transporter type 2 (VMAT2)PET ligand 18F-florbenazine (Avid Radiopharmaceu-ticals, Lilly) ongoing.

Seven Phase II clinical trials of disease modifyingdrugs, of monoclonal antibodies against A� BAN-2401, crenezumab, GSK-93377A, i.v. octagam,ponezumab, and of vaccines against A� AFFITOPE-AD-02 and CAD-106 are underway. This applies alsofor the three Phase II clinical trials of small moleculespreventing A� aggregation or inhibiting formation oftransthyretin amyloid fibrils, as doxycycline hyclate(see [7]), ELND-005 (see [7]), or preventing tau aggre-gation as PBT-2 (see [7]).

Concerning drugs for the palliative treatment ofAD four Phase III compounds are currently fron-trunners, ARC-029 (voltage-gated channel blocker),DP-b99 (a calcium and zinc chelator), SK-PC-B70M(a natural product, see [7]) and TRI-102-ADD-001(a nootropic) followed by 28 Phase II compounds(excluding stem cell preparations), apabetalone (agene expression stimulator), RNS-60 and ST-101(voltage-gated channel blockers), CERE-110, GM-609 and T-817MA (trophic factor stimulators),BN-82541, MitoQ (see [7]), MTP-131 (see [7]),and VP-20629 (antioxidants), circadin (see [7]), (-)-clausenamide, KD-501 (see [7]), PPL (see [7]),resveratrol (see [7]), RPh-201 (see [7]), sodiumoligomannurarate, STA-1 and VR-040 (see [7],natural products), LND-101001, N-251a (see [7]),PXT-864, TPM-189 (see [7]), and VI-1121 (see [7],nootropics), AM-111 (see [7]), davunetide, NK-001(see [7]), and NNZ-2566 (peptides).

DISCLOSURE STATEMENT

Author’s disclosures available online (http://www.j-alz.com/disclosures/view.php?id=2388).

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Cognitive Enhancers (Nootropics). Part 3: Drugs ...€¦ · nootropics, peptides, psychostimulants, stem cells, tau, vaccines INTRODUCTION As of June 14, 2014, there are 28,317 entries