Tauists, Baptists, Syners, Apostates,and New Data

Recognition of a common mechanistic theme sharedby Alzheimer’s disease (AD) and other neurodegenera-tive disorders began to emerge in the last decade, andbecause many of these disorders are characterized neu-ropathologically by intracellular and/or extracellular ag-gregates of proteinaceous fibrils that are implicated inprogressive brain degeneration, these disorders mayshare similar targets for drug discovery.1 Thus, despitedifferences in the molecular composition of these fila-mentous lesions, growing evidence suggests that similarpathological mechanisms may underlie all of these dis-orders. More specifically, the onset and/or progressionof brain degeneration in AD and other neurodegenera-tive disorders may be linked mechanistically to abnor-mal interactions between brain proteins that lead totheir assembly into filaments and the aggregation ofthese filaments within brain cells or in the extracellularspace.

In sporadic and familial AD (FAD), these filamen-tous lesions are exemplified by intracytoplasmic neuro-fibrillary tangles (NFTs) and extracellular amyloid orsenile plaques. Although filamentous lesions are recog-nized as diagnostic hallmarks of specific disorders, spo-radic AD and FAD illustrate some of the complex andpoorly understood overlap among these neurodegenera-tive diseases.2,3 For example, the heterogeneous de-menting disorders classified as AD overlap with a largegroup of distinct neurodegenerative disorders (knownas tauopathies) that are characterized by prominent�-rich tangle pathology throughout the brain as well aswith another diverse group of disorders (known assynucleinopathies) that are characterized by filamen-tous �-synuclein brain pathology.2–4 Thus, whereasthe diagnostic hallmarks of AD are numerous senileplaques composed of A� fibrils and intraneuronalNFTs formed by aggregated � filaments, NFTs aresimilar to the filamentous � inclusions characteristic ofneurodegenerative tauopathies, many of which do notshow other diagnostic disease-specific lesions. Notably,� gene mutations have been shown to cause familialfrontotemporal dementia and parkinsonism linked tochromosome 17 in many kindreds.4 Moreover, whereasLewy bodies (LBs) are regarded as hallmark intracyto-plasmic neuronal inclusions of Parkinson’s disease(PD), they also occur in the most common subtype ofAD known as the LB variant of AD, and numerouscortical LBs are the defining brain lesions of dementiawith LBs, which is similar to AD clinically, but distinct

from AD pathologically.2,3 Furthermore, �-synucleingene mutations cause familial PD in rare kindreds, andthese mutations may be pathogenic by altering theproperties of �-synuclein, thereby promoting the for-mation of �-synuclein filaments that aggregate intoLBs. However, it is now known that FAD mutationsand trisomy 21 lead to abundant accumulations of LBscomposed of �-synuclein filaments in the brains ofmost FAD and elderly Down’s syndrome patients, re-spectively, but it is unclear how these genetic abnor-malities promote the formation of LBs from wild-type�-synuclein proteins encoded by a normal gene.2,3

Nonetheless, the accumulation of �-synuclein into fil-amentous inclusions appears to play a mechanistic rolein the pathogenesis of several progressive neurologicaldisorders including PD, dementia with LBs, Down’ssyndrome, FAD, LB variant of AD, sporadic AD, mul-tiple system atrophy, and other synucleinopathies.

Thus, many neurodegenerative diseases share anenigmatic symmetry, that is, missense mutations in thegene encoding the disease protein cause a familial vari-ant of the disorder as well as its hallmark brain lesions,but the same brain lesions also form from the corre-sponding wild-type brain protein in sporadic variantsof the disease. Accordingly, clarification of this enig-matic symmetry in any one of these disorders is likelyto have a profound impact on understanding themechanisms that underlie other of these diseases andon efforts to develop novel therapies to treat them.Moreover, AD is one of the more striking examples ofa “triple brain amlyloidosis,” that is, a neurodegenera-tive disorder wherein at least three different buildingblock proteins (�, �-synuclein) or peptide fragments(A�) of a larger A� precursor protein (APP) fibrillizeand aggregate into pathological deposits of amyloidwithin (NFTs, LBs) and outside (senile plaques) neu-rons. However, there are examples of other triple brainamyloidoses such as Down’s syndrome and Mariana Is-land dementia or Guam Parkinson’s dementia complexthat also show evidence of accumulations of amyloiddeposits formed by �, �-synuclein, and A�, and thereis increasing recognition that � and �-synuclein intra-neuronal inclusions may converge with or without ex-tracellular deposits of A� in “double brain amyloid-oses” as exemplified by the abundant � inclusions in amember of the Contursi kindred with familial PD, orthe co-occurrence of PD with abundant A� deposits

© 2002 Wiley-Liss, Inc. 263

and dementia or with progressive supranuclear palsy insome patients.5–9

Furthermore, in this issue Saito and colleagues re-port detection of A� deposits in patients withNiemann-Pick type C (NPC) disease, a hereditary dis-order in which some long-lived patients develop a de-mentia that was thought to be associated with the pres-ence of NFTs and no other forms of brain amyloid.10

Thus, this is yet another example of a familial braindisorder in which pathogenic mutations in two differ-ent genes (ie, NPC1 and HE1) lead to the accumula-tion of brain amyloid deposits formed by protein prod-ucts of seemingly unrelated genes (ie, tau and APP) ondifferent chromosomes that are linked to neurodegen-eration. More remarkably still, Saito and colleagues re-port the presence of A� deposits in the brains of NPCpatients with NFTs who were 5 to 11 years younger(31, 32, and 37 years old) than control subjects whofirst showed A� deposits in their brains at age 42years.10 Although NPC is suspected of being inducedby genetic mutations that perturb lipid metabolism,11

it is the third example of a neurodegenerative tauopa-thy (the others being Guam Parkinson’s dementiacomplex, and frontotemporal dementia and parkinson-ism linked to chromosome 17) in which it might beargued that the early accumulation of NFTs coulddrive the latter occurrence of A� deposits.8,12 Takentogether, these disorders call into question the logic ofthe A� amyloid cascade hypothesis, a major tenet ofwhich is that the formation of NFTs is induced by thefibrillization and accumulation of A�.13–17 However,the A� amyloid cascade hypothesis has been controver-sial almost since it was first articulated,13–17 and de-bates about the validity of this hypothesis have been sovigorous between its advocates (ie, the so-called�-Amyloid Peptide proponents or “BAPtists”) andnonbelievers or those who assert � inclusions are theprimary driving force of brain degeneration (ie, the so-called TAUists) that they have been likened to religiouszealots.18,19 Indeed, with the recognition that�-synuclein is the building block of LBs and relatedamyloid-like inclusions in PD, AD and other relateddisorders, a third faction (ie, so-called SYNers) mayjoin in this debate about which form of amyloid ismost upstream in the cascade of events leading to neu-rodegeneration. This notwithstanding, reports such asthe one by Saito and colleagues imply that the A�amyloid cascade hypothesis may be ripe for apostasynow, and that a truly informed view of the sequence ofevents leading to brain degeneration in triple and dou-ble brain amyloidoses must await the emergence ofmore new data from experimental studies (eg, in cellculture and animal model systems) that rigorously testcompeting hypotheses about the cascade of events lead-ing to brain degeneration in these disorders.

There is no doubt that tests of these competing hy-

potheses have considerable urgency for the discovery ofmore effective therapies for AD, PD, and related dis-orders, including NPC. Moreover, there is no shortageof alternative hypothetical upstream events that mightunderlie protein fibrillization and aggregate formationsuch as increased intracellular oxidative stress coupledwith a failure of normal cellular antioxidant mecha-nisms or impairments in molecular chaperones andprotein refolding mechanisms.20–24 Indeed, there maybe a plethora of pathways leading to protein misfoldingwith the subsequent formation of toxic amyloid depos-its, and a much larger array of proteins than previouslyanticipated may be vulnerable to fibrillization andcause disease as a result of a variety of noxious orstressful cellular perturbations.25 Thus, more new datafrom intensified research efforts are critically needed tounderstand these processes in greater detail if we are todevelop more effective therapies for protein misfoldingdiseases including neurodegenerative brain amyloidosessuch as AD, synucleinopathies, and tauopathies. Forexample, compounds have been identified that preventthe conversion of normal proteins into abnormal con-formers or variants with conformations that predisposethe pathological proteins to form potentially toxic fila-mentous aggregates,26–28 and it is also plausible tospeculate that some of these agents may have therapeu-tic efficacy in more than one neurodegenerative disor-der. As the implications of more profound insights intoabnormal protein–protein interactions and protein mis-folding coalesce from continuing research advances,there will be brighter prospects for the discovery ofnew and better therapies for AD and for other devas-tating neurodegenerative disorders caused by abnormalfilamentous aggregates.

Additional information on the neurodegenerative diseases reviewedhere also can be obtained by visiting the Center for Neurodegen-erative Disease Research Web site (http://www.med.upenn.edu/cndr).

The studies summarized here from my laboratory were supported bygrants from the National Institute on Aging of the National Insti-tutes of Health and the Alzheimer’s Association.

I thank Dr Virginia M.-Y. Lee, members of the Center for Neuro-degenerative Disease Research (CNDR), and the many CNDR col-laborators within and outside the University of Pennsylvania for im-portant contributions to the studies reviewed here. I also express myappreciation to the families of the many patients studied by CNDRinvestigators over the past decade who have made it possible to pur-sue many of the research advances discussed here.

John Q. Trojanowski, MD, PhD

Center for Neurodegenerative Disease ResearchDepartment of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphia, PA

264 Annals of Neurology Vol 52 No 3 September 2002

References1. Trojanowski JQ, Lee VM-Y. “Fatal attractions” of proteins: a

comprehensive hypothetical mechanism underlying Alzheimer’sdisease and other neurodegenerative disorders. Ann N Y AcadSci 2000;924:62–67.

2. Galvin JE, Lee VM-Y, Trojanowski JQ. Synucleinopathies:clinical and pathological implications. Arch Neurol 2001;58:186–190.

3. Kotzbauer PT, Trojanowski JQ, Lee VM-Y. Lewy body pathol-ogy in Alzheimer’s disease. J Molec Neurosci 2001;17:225–232.

4. Lee VM-Y, Goedert M, Trojanowski JQ. Neurodegenerativetauopathies. Annu Rev Neurosci 2001;24:1121–1159.

5. Duda JE, Giasson BI, Mabon M, et al. Concurrence of alpha-synuclein and tau pathology in a Contursi kindred brain. ActaNeuropathol (DOI 10.1007/S00401-002-0522-2).

6. Forman MS, Schmidt ML, Kasturi S, et al. Tau and alpha-synuclein pathology in amygdala of ALS/PDC patients ofGuam. Am J Pathol (in press).

7. Judkins AR, Forman MS, Uryu K, et al. Co-occurrence of Par-kinson’s disease with progressive supranuclear palsy. Acta Neu-ropathol 2002;103:525–530.

8. Schmidt ML, Lee VM-Y, Saido T, et al. Amyloid plaques inGuam amyotrophic lateral sclerosis/parkinsonism-dementiacomplex contain species of A� similar to those found in theamyloid plaques of Alzheimer’s disease and pathological aging.Acta Neuropathol 1998;95:117–122.

9. Yamazaki M, Arai Y, Baba M, et al. Alpha-synuclein inclusionsin amygdala in the brains of patients with the parkinsonism-dementia complex of Guam. J Neuropathol Exp Neurol 2000;59:585–591.

10. Saito Y, Suzuki K, Nanba E, et al. Niemann-Pick type Cdisease: accelerated neurofibrillary tangle formation and amy-loid � deposition associated with Apolipoprotein E ε4 homozy-gosity. Ann Neurol 2002;52:350–354.

11. Nasreddine ZS, Loginov M, Clark L, et al. From genotype tophenotype: a clinical, pathological and biochemical investiga-tion of frontotemporal dementia with parkinsonism (FTDP-17)caused by the P301L tau mutation. Ann Neurol 1999;45:704–715.

12. Liscum L. Niemann-Pick type C mutations cause lipid trafficjam. Traffic 2000;1:218–225.

13. Hardy J. Amyloid, the presenilins and Alzheimer’s disease.Trends Neurosci 1997;20:154–159.

14. Hardy J, Allsop D. Amyloid deposition as the central event inthe aetiology of Alzheimer’s disease. Trends Pharmcol Sci 1991;12:383–388.

15. Hardy J, Duff K, Hardy KG, et al. Genetic dissection of Alz-heimer’s disease and related dementias: amyloid and its relation-ship to tau. Nat Neurosci 1998;1:355–358.

16. Huse JT, Doms RW. Closing in on the amyloid cascade: recentinsights into the cell biology of Alzheimer’s disease. Mol Neu-robiol 2000;22:81–98.

17. Sommer B. Alzheimer’s disease and the amyloid cascadehypothesis: ten years on. Curr Opin Pharmacol 2002;2:87–92.

18. Lee VMY. Tauists and BAPtists united—well almost! Science2001;293:1446–1447.

19. Mudher A, Lovestone S. Alzheimer’s disease—do tauists andbaptists finally shake hands? Trends Neurosci 2002;25:22–26.

20. Auluck PK, Chan HYE, Trojanowski JQ, et al. Chaperone sup-pression of alpha-synuclein toxicity in a Drosophila model ofParkinson’s disease. Science 2002;295:865–868.

21. Giasson BI, Lee VM-Y, Ischiropoulos H, Trojanowski JQ. Therelationship between oxidative/nitrative stress and pathologicalinclusions in Alzheimer’s and Parkinson’s disease. Free RadicBiol Med (in press).

22. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s dis-ease. Free Radic Biol Med 1997;20:154–159.

23. Pratico D, Clark CM, Liu F, et al. Subjects with mild cognitiveimpairment have increased brain oxidative stress. Arch Neurol(in press).

24. Welch WJ, Gambetti P. Chaperoning brain diseases. Nature1998;392:23–24.

25. Bucciantini M, Giannoni E, Chiti F, et al. Inherent toxicity ofaggregates implies a common mechanism of protein misfoldingdisease. Nature 2002;416:507–511.

26. Irizarry MC, Hyman BT. Alzheimer disease therapeutics.J Neuropath Exper Neurol 2001;60:923–928.

27. Mayeux R, Sano M. Treatment of Alzheimer’s disease. N EnglJ Med 1999;341:1670–1679.

28. Trojanowski JQ. Emerging Alzheimer’s disease therapies: focus-ing on the future. Neurobiol Aging (in press).

DOI: 10.1002/ana.10281

Trojanowski: Editorial 265