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Biological Research Centre Address: H-6726 Szeged, Temesvári krt. 62. Mail: H-6701 Szeged, POB 521. www.brc.hu
„Az élettudományi-klinikai felsőoktatás gyakorlatorientált és hallgatóbarát korszerűsítése a vidéki képzőhelyek nemzetközi versenyképességének erősítésére”
program keretében finanszírozott
ELŐADÁS KIVONAT
CLASSROOM LECTURE HANDOUT
financed by the program
„Practice-oriented, student-friendly modernization of the biomedical education for strengthening the international competitiveness of the rural Hungarian universities”
Dátum / Date:
2016. OKTÓBER 19. / OCTOBER 19, 2016
Helyszín / Place:
MTA SZBK BIOFIZIKAI INTÉZET, TANÁCSTEREM / LECTURE ROOM, INST. OF BIOPHYSICS, BIOLOGICAL RESEARCH CENTRE
SZEGED, TEMESVÁRI KRT. 62.
Az előadás címe / Title of the presentation:
HEAT SHOCK PROTEINS AND THEIR ROLE IN HUMAN DISEASES
Előadók / Speakers:
MELINDA E. TÓTH, MIKLÓS SÁNTHA
M.E. Tóth, M. Sántha October 19, 2016
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Heat shock proteins and their role in human diseases
part I.The heat shock proteins
Melinda E. TóthInstitute of Biochemistry
October 19, 2016
„Practice-oriented, student-friendly modernization of the biomedical education for strengthening the international competitiveness of the rural Hungarian universities”TÁMOP-4.1.1.C-13/1/KONV-2014-0001
Heat shock proteins (Hsps)
Ubiquitously expressed, evolutionarily conserved chaperone proteins.
Heat shock response was first observed in the Drosophila buscii salivary gland chromosomes by Ritossa in 1962.
Hsps can be induced by heat, heavy metal or ethanol treatment, hypoxia, ischemia, and they are also upregulated in several diseases and infections.
Their most important function is to protect cells from the toxic effects of stress.
Ferruccio Ritossa
De Maio et al. Cell Stress and Chaperones (2012) 17:139–143
Preconditioning: a mild, sublethal heat-stress can induce the expressionof Hsp and increase cell survival after a subsequent, normally lethal heat treatment.
Chaperone functions of Hsps
Muchowski and Wacker (2005) Nat Rev Neurosci. 6:11-22.
Hsps play roles in normal cellular homeostasis and development.
They regulate the biosynthesis, folding/unfolding, transport and assembly of cellular proteins.
They facilitate the degradation of certain abnormal proteins.
They participate in antigen presentation.
They are also implicated in differentsignal transduction pathways.
M.E. Tóth, M. Sántha October 19, 2016
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During stress conditions, Hsps help to prevent the change of the conformation of other proteins.
They protect uncorrectly folded proteins against aggregation.
Upon recovery they facilitate the refolding of misfolded proteins.
They assist in the proteasomal degradation of peptides that can not be refolded.
Hsps also have roles in membrane protection during stress conditions, and they have anti-apoptotic functions
Muchowski and Wacker (2005) Nat Rev Neurosci. 6:11-22.
Heat shock protein families
- small Hsp (sHsp, HSPB)- Hsp70 (HSPA)- Hsp40 (DNAJ)- Hsp110 (HSPH)- Hsp90 (HSPC)- chaperonin families (Hsp60)
Rutherford (2003)Nat Rev Genet. 4:263-74.
Small heat shock (HspB) protein family
Gusev et al. (2002)Biochemistry 67:511-519.
Molecular weights between 16-40 kDa.
α-crystallin domain : a conserved C-terminal domain of 100 amino acids.
α-crystallin domain
Mammalian small Hsp family consists of 11 members.
They usually form homo- or heterooligomeric complexes up to ~700 kDa.
Post-translational modifications: phosphorylation on serine residues.
M.E. Tóth, M. Sántha October 19, 2016
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Functions of sHsps
Wilhelmus et al. (2007)Mol Neurobiol. 35:203–216
Stabilize the cytoskeleton and membranes during stressconditions.
Protect cells from apoptosis and oxidative stress.
Bind to partially denatured proteins and prevent their aggregation, maintaining them in a refolding competent state.
ATP independent chaperones.
Hsp70 (HspA) protein family
Protein Alternativenames
Homology toHspA1A
Cellular localization Stress-induced
HspA1A Hsp70, Hsp72, Hsp70-1
100 Cytosol, nucleus, lysosomes
Yes
HspA1B Hsp70, Hsp72, Hsp70-2
99 Cytosol, nucleus, lysosomes
Yes
HspA1L Hsp70-Hom 90 Cytosol, nucleus No
HspA2 Hsp70-3 84 Cytosol, nucleus No
HspA5 BiP, GRP78 64 ER No
HspA6 Hsp70B’ 85 Cytosol, nucleus Yes
HspA8 Hsc70, Hsp73 86 Cytosol, nucleus No
HspA9 GRP75, mtHsp75, mortalin
52 Mitochondria No
Based on Daugaard et al. (2007)FEBS Letters 581:3702–3710
Functions of Hsp70
Nollen and Morimoto (2002)Journal of Cell Science 115:2809-2816
During stress conditions one Hsp70 participates in the refolding of the denatured proteins.
Hsp70 contains two functional units:
M.E. Tóth, M. Sántha October 19, 2016
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Csermely and Yahara (2002)Molecular Pathomechanisms and New Trends in Drug Research, Taylor and Francis, London and New York, pp 67-75.
Catalytic cycle of Hsp70
Hsp40 (DnaJ) protein family
Largest human Hsp family (50 members,three subgroups) Type I (DnaJA)
Type II (DnaJB)
Type III (DnaJC)
J domain Gly/Phe-rich region Cys repeats
Based on Qiu et al. (2006) Cell. Mol. Life Sci. 63:2560–2570and Kampinga et al. (2009) Cell Stress Chaperones 14:105–111
Conserved,N-terminal J-domain, through which they bind to Hsp70 proteins
Qiu et al. (2006) Cell. Mol. Life Sci. 63:2560–2570
Hsp40 proteins can bind substrate peptides and transfer them to Hsp70, while the J-domain promotes ATP hydrolysis.
Csermely and Yahara (2002)Molecular Pathomechanisms and New Trends in Drug Research, Taylor and Francis, London and New York, pp 67-75.
M.E. Tóth, M. Sántha October 19, 2016
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Hsp110 (HspH) protein family
Protein Alternative names Cellularlocalization
HspH1 Hsp105 Cytosol
HspH2 HSPA4, APG-2, HSP110 Cytosol
HspH3 HSPA4L, APG-1 Cytosol
HspH4 Grp170, ORP150, HSP12A
ER
Based on Kampinga et al. (2009)Cell Stress Chaperones 14:105–111 Liu and Hendrickson (2007) Cell 131:106-120
Functions:- ‘holdases’, they recognize and bind denatured proteins maintaining them in a
refolding-competent state- nucleotid exchange factors for Hsp70, removing ADP after ATP hydrolysis.
Protein Alternative names Cellularlocalization
HspC1 HSP89, HSP90 Cytosol
HspC2 HSP90α Cytosol
HspC3 HSP90B, HSP90β Cytosol
HspC4 GRP94, endoplasmin ER
HspC5 TRAP1, HSP75
Hsp90 (HspC) protein family
Based on Kampinga et al. (2009) Cell Stress Chaperones 14:105–111and Csermely et al. (1998) Pharmacol. Ther. 79:129–168
Csermely et al. Pharmacol. Ther. 79:129–168, 1998
1-2% of total cellular proteins
Functions of Hsp90
Whitesell and Lindquist (2005)Nature Reviews Cancer 5:761-772
- suppress the aggregation of unstable proteins
- disaggregate loose protein aggregates
- regulate cellular signalling
M.E. Tóth, M. Sántha October 19, 2016
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HSF
HSE
Hsps
Transcriptional regulation of Hsps
Heat shock factors (HSFs)- special transcription factors
Heat shock elements (HSEs) are located in the promoter region of the Hsps
Based on Morimoto (1998) Genes Dev. 12:3788-3796
HSF
HSFHSF
Organisms Expression
HSF1 Human, mouse, chicken ubiquitous
HSF2 Human, mouse, chicken ubiquitous
HSF3 Chicken, mouse ubiquitous
HSF4 Human tissue-specific: heart, skeletal muscle, brain
Based on Morimoto (1998) Genes Dev. 12:3788-3796and Westerheide et al. (2012) Current Protein and Peptide Science 13:86-103
DNA bindingdomain
Transactivationdomains
Trimerizationdomains
Regulatory domain
Westerheide et al. (2012) Current Protein and Peptide Science 13:86-103
Csermely and Yahara (2002)Molecular Pathomechanisms and New Trends in Drug Research, Taylor and Francis, London and New York, pp 67-75.
M.E. Tóth, M. Sántha October 19, 2016
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Vígh et al. (2007) Trends Biochem Sci. 32:357-63
Role of Hsps in human diseases:Chaperone function
Native proteinMisfolded protein
Aggregates
sHsp oligomeric complexes with misfolded proteins
Hsp70-Hsp40substrate complex
Proteasoma
Hsp70Hsp40
sHsp
Vígh et al. (2007) Trends Biochem Sci. 32:357-63
Membrane quality control
M.E. Tóth, M. Sántha October 19, 2016
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Membrane quality control
Based on Nakamoto and Vígh (2007) Cell. Mol. Life Sci. 64:294–306
Oxidative stress
Oxidative stress
Aging
Neurodegenerativedisorders Stroke
Myocardialinfarction
Diabetes
Cancer
Oxidative stress
Protein oxidationLipid peroxidation DNA damage Cytoskeletaldamage
ROS
GSH
Protein aggregation
Oxidative stress
M.E. Tóth, M. Sántha October 19, 2016
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Oxidative stress
Protein oxidationLipid peroxidation DNA damage Cytoskeletaldamage
ROS
GSH
Protein aggregation
sHsps
Proteasomaldegradation
Oxidative stress
Apoptosis
Ischia and So 2013 Nature Reviews Urology 10:386-395
Ischemia/reperfusion injury
Ethanol induced cytotoxicity
Ageing and neurodegenerative disorders
Obesity and diabetes
Cancer
Role of Hsps in human diseases:
M.E. Tóth, M. Sántha October 19, 2016
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Ischemia/reperfusion injury
Ischemia
ATP production
Anaerobicglycolysis
Calciumaccumulation
Loss of membrane
integrity
Mitochondrialdysfunctions
ROS generation
Reviewed in Nishizawa and Nagata 2000
HSF1
Hsp70
HSF1
HSF1HSF1
Hsp90Hsp27
Ischemia/reperfusion injury
Role of Hsps in post-ischemic recovery in heart
Currie et al. 1988:
Source:http://www.meditec.hia.rwth-aachen.de/
42 °C
24 hours
Ischemic perfusion
improved myocardial recovery
reduced mithocondrial damageincreased Hsp70 expression
M.E. Tóth, M. Sántha October 19, 2016
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Treatment Organism Effect Ref.Heat shock pretreatment
Rat heart Reduced infarct size Donnelly et al. 1992
Sublethal ischemic or heat pretreatment
Rabbit heart Reduced infarct size Marber et al. 1993
Hsp70 overexpression Primary rat cardiocytes Increased cell survival Cumming et al. 1996
Hsp27 or αB-crystallin overexpression
Rat cardiomyocytes Increased cell survival Martin et al. 1997
Hsp70 overexpression Mice heart Improved post-ischemic myocardial recovery, decreased cellular injury
Plumier et al. 1995
Hsp27 overexpression Mice heart Preserved contractile function, decreased oxidative stress
Hollander et al. 2004
Bimoclomol (Hsp inducer) treatment
Rat heart Antiischemic, antiarrhythmic effect
Vígh et al. 1997
Exercise training Rat heart Decreased myocardial lipid peroxidation
Demirel et al. 1998
Role of Hsps in post-ischemic recovery in heart
Treatment Organism Effect Ref.
Ischemic pretreatment Gerbil brain Decreasedhippocampal cell death
Kitagawa et al. 1990
Transgenicoverexpression of Hsp70
Mice brain Reduced neuronaldamage
Plumier et al. 1997
Viral overexpression of Hsp70
Rat brain Improved neuronsurvival
Yenari et al. 1998
Geldanamycin (Hspinducer) treatment
Rat brain Reduced infarctvolume and cell death
Lu et al. 2002
Role of Hsps in ischemic brain damage
Increased membrane fluidity
Protein denaturation
Cytotoxic effects of ethanol
ROS
Apoptotic cell death
Cytoskeleton
M.E. Tóth, M. Sántha October 19, 2016
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Ethanol induced apoptotic cell death
Zhou et al. (2001) Am J Pathol. 159:329–338.
Ikonomidou et al. (2000) Science 287:1056-60.
Inhibition of cytochrome c release
Inhibition of caspase 3and caspase 9 activation
Hsp
Increased membrane fluidity
Protein denaturation
hsp gene
mRNA
HSE
HSF
HSF activation
Alcohol stress
Maintenance of membrane stability Prevention of protein denaturation/ aggregation
Protective effects of Hsps
Tóth et al. (2014) Cell Stress Chaperones 19:299-309.
Aging and neurodegenerative diseases
Native proteinMisfolded protein
sHsp oligomeric complexes with misfolded proteins
Hsp70-Hsp40substrate complex
Proteasoma
Hsp70
Hsp40
sHsp
Normal protein homeostasis
M.E. Tóth, M. Sántha October 19, 2016
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Aging and neurodegenerative diseases
Native proteinMisfolded protein
sHsp oligomeric complexes with misfolded proteins
Hsp70-Hsp40substrate complex
Proteasoma
Hsp70
Hsp40sHsp
Aging
Aggregates
Protein-misfolding disorders
Disease Protein Localization of aggregates
Alzheimer’s disease (AD) Amyloid-β Intra- and extracellular
Alzheimer’s disease (AD) Hyperphosphorylatedtau
Intracellular
Parkinson’s disease (PD) α-synuclein Intracellular
Huntington’s disease (HD) Huntingtin Intracellular
Amyotrophic lateralsclerosis (ALS)
Superoxide dismutase(SOD)
Intracellular
Prion disease Prion protein Extracellular
Mattson (2004)Nature 430:631-9.
M.E. Tóth, M. Sántha October 19, 2016
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Aggregation of amyloid
Muchowski and Wacker (2005) Nat Rev Neurosci. 6:11-22.
Muchowski and Wacker (2005) Nat Rev Neurosci. 6:11-22.
Disease model Treatment Effect Ref.APPsw mouse model of AD Hsp70 overexpression Improved cognitive function,
reduced plaque formationand neuronal loss
Hoshino et al. 2011
APPsw/Psen1 mousemodel of AD
Hsp27 overexpression Improved cognitive and synaptic functions, reducedplaque formation
Tóth et al. 2013
SOD1-G93A mouse modelof ALS
Arimoclomol treatment Improved muscle function, increased life span
Kieran et al. 2004
Rat model of PD GRP78 overexpression Reduced α-syn neurotoxicityand apoptosis
Gorbatyuk et al. 2012
R6/2 mouse model of HD DNAJB2a overexpression Reduced mutant huntingtinaggregation, improved neurological performance
Labbadia et al. 2012
R6/2 mouse model of HD HSF1 overexpression Increased life span Fujimoto et al. 2005
Role of Hsps in neurodegenerative diseases
Reviewed in Kakkar et al. (2014) Dis Model Mech. 7:421-34.
M.E. Tóth, M. Sántha October 19, 2016
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Obesity and diabetes
Diabetes
Chronicstress state
Disturbedprotein
homeostasis
Oxidativestress
ER stress
Impairedstress
response
Protein aggregation
Hsps
Protein glycation
Heat shock response and diabetes
Hooper 1999:
Hot tub treatment for 30 min daily for 3 weeks
Improved fasting glucose
Relief ofneuropathic symptoms1 % drop in HbA1
Trend toward weight loss
Treatment Model Effect Ref.
Far infrared lighttherapy
diabetic mice(db/db)
Improved obesity related insulinresistance
Kokura et al. 2007
Electric heating blanket Fat fed mice Prevented diet inducedhyperglycemia, hyperinsulinemiaand insulin resistance
Chung et al. 2008
Hot water immersion Fat fed rats Improved glucose tolerance, insulin-stimulated glucosetransport
Gupte et al. 2009
BGP-15 treatment Leptin-deficient(ob/ob) mice
Reduced fasting levels of glucoseand insulin
Chung et al. 2008
BGP-15 treatment Insulin-resistantpatients
Increased insulin sensitivity and glucose utilization
Literáti-Nagy et al. 2009
Bimoclomol treatment Streptozoicintreated diabeticrats
Improved wound healing Vígh et al. 1997
Heat shock response and diabetes
M.E. Tóth, M. Sántha October 19, 2016
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Cancer
Poor blood supply
Inadequate glucose, oxygen and pH level
Chemotherapy, radiotherapy
Hsps
Good prognosis Poor prognosis No correlation
Hsp27 expression endometrialadenocarcinomas, oesophageal cancer,malignant fibrous histiocytomas
ovarian, gastric, liverand prostate cancer, and osteosarcomas
head and necksquamous cancer, bladder, renal cancer, leukemia
Hsp70 expression oesophageal cancer, pancreatic cancer, renal cancer,and melanoma
breast, endometrial, uterine cervicalcancer, transitional cell carcinoma of the bladder
ovarian, oral, headand neck squamous cancer, gastric and prostate cancer,leukemia
Hsp90 expression endometrial cancer breast cancer ovarian and oralcancer
Prognostic implications of Hsps
Reviewed by Ciocca and Calderwood (2005) Cell Stress Chaperones 10:86–103
Response to anticancer therapies
Hspoverexpression
Preventing apoptotic celldeath of the tumor cells(doxorubicin treatment)
Refolding/stabilizingdenatured proteins
(herceptin treatment)
Improving DNA repair
Inhibition or downregulation of Hspsseems to be a possible treatment
additional to traditionalchemotherapy (quercetin, OGX-427)
M.E. Tóth, M. Sántha October 19, 2016
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Tumor immunotherapy based on Hsps
Zhang and Zheng (2013) Oncology Letters 6:1543-1549
Part II.
The cardio- and neuroprotective roles of a smallheat shock protein, Hsp27.
(in vivo studies)
Miklos SanthaInstitute of Biochemistry
October 19, 2016
„Practice-oriented, student-friendly modernization of the biomedical education for strengthening the international competitiveness of the rural Hungarian universities”TÁMOP-4.1.1.C-13/1/KONV-2014-0001
Production of Hsp27 transgenic mice
(Based on the protocol of UC San Diego Health System)
M.E. Tóth, M. Sántha October 19, 2016
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vektorCMV Hsp27 bGHpA
Physical map of the transgene
c
(source: http://card.medic.kumamoto-u.ac.jp/)
Fertilized mouse oocytes
(source: http://acces.ens-lyon.fr/biotic/procreat/clonage/html/TechniquesTransgenese.htm)
Pronucleus microinjection
M.E. Tóth, M. Sántha October 19, 2016
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Production of Hsp27 transgenic mice
(Based on the protocol of UC San Diego Health System)
Production of Hsp27 transgenic mice
Two independent transgenic lines (24 and 33) wereidentified using PCR
Hsp27
Analysis of Hsp27 expression in transgenic offsprings using Western blot
• Total protein from brain and heart tissues was purified
Hsp27
M.E. Tóth, M. Sántha October 19, 2016
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Doxorubicin
source: http://elifesciences.org/
Patel and Kaufmann, 2012. eLife 2012;1:e00387
source:http://chem257.pbworks.com/
Effect of Doxorubicin on cardiomyocytes
source: http://biomedfrontiers.org/
Dimitrakis et al. 2012. Cell and tissue research, 350(2):361-372.
Cardioprotective role of Hsp27 after doxorubicin treatment
Tunnel assay(DNA fragmentation)
M.E. Tóth, M. Sántha October 19, 2016
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Expression of Hsp27 in the brain of transgenic mice
Tóth et al. 2010. Cell Stress Chaperons 15. (6):807-17
Is there a neuroprotective role of Hsp27?
Acut alcohol treatment(20% ethanol ip.)
Improved motor coordinationfootprint analysisbalance –beam walkinginverted screen testswimming test
Tóth et al. 2010. Cell stress Chaperons 15. (6):807-17
Behavioural tests• To investigate the effect of acute ethanol administration
by analysing ataxia, muscle strength and motor coordination
• Four groups : EtOH inj. wild-type EtOH inj tg, saline inj wild-type saline inj tg ,n=10 mice / group
• Before test mice were trained three times
• 2 g/kg i.p. injection of 20% EtOH,
• In three out of the 5 tests one-way ANOVA revealed a significant difference between the transgenic and wild type mice
M.E. Tóth, M. Sántha October 19, 2016
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Footprint analysis• Stepping patterns were compared• 60 cm long 7 cm wide runner • Lined with white paper• the fore- and hind-paws of the animals were covered with different colors
of non-toxic paints• middle steps of a series of steps were analysed (6 step)• For quantitative comparsion of footprint patterns, stride length and width
of front and back leg and front/hind paw overlap were measured
Results of footprint assay• EtOH injected wild type
mice tend to walk on whole paw
• and produced toe dragging
• footprint of EtOH injected transgenic mice were much similar to the pattern of saline injected mice
• Significant difference in the stride length• significantly impaired forelimb-hindlimb coordination in the EtOH injected wild
type group
• There is no significant difference in the results of females
M.E. Tóth, M. Sántha October 19, 2016
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Balance beam test• Coordination and balance
• 1m long 10mm round horizontal wooden beam
• Time taken to run along the beam, slips and falling-off were recorded
• Three trials
Time taken to run along the beam
Performance in balance beam test
• In this test 86% of wild type mice fell off at least once from the beam, while in the transgenic group only 53%.
• In the wild type group mice fell off more then two times in average, while in the transgenic group less then once
M.E. Tóth, M. Sántha October 19, 2016
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Inverted screen test
• coordination and strength
• 25x30 cm wire mesh elevated 50 cm above the ground
• Mice not climbing to the top were considered to have reduced strength or coordination
Result of inverted screen test
• Almost all EtOH injected wild type mice fell off the screen
• 43% of the EtOH treated transgenic mice could climb over the edge of the screen (50% of males and 26% of females)
Is there a neuroprotective role of Hsp27?
Acut alcohol treatment(20% ethanol ip.)
Improved motor coordinationfootprint analysisbalance –beam walkinginverted screen testswimming test
Tóth et al. 2010. Cell stress Chaperons 15. (6):807-17
Less neuronal deathFluoroJade staining of cortical and hippocampalslices
Tóth et al. 2010. Cell stress Chaperons 15. (6):807-17
Chronic alcohol consumption (20% ethanol for 5 weeks)
M.E. Tóth, M. Sántha October 19, 2016
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Neuronal death after chronic ethanol consumptionhippocampus cortex
Tóth et al. 2010. Cell Stress Chaperons 15. (6):807-17
Wt EtOH
Wt control
Tg EtOH
Tg control
cerebellum
Is there a neuroprotective role of Hsp27?
Acut alcohol treatment(20% ethanol ip.)
Improved motor coordinationfootprint analysisbalance –beam walkinginverted screen testswimming test
Tóth et al. 2010. Cell stress Chaperons 15. (6):807-17
Alzheimer’s disease(APPSwexPse1 (AD) x Hsp27 mice)
Improved learning and memoryBarnes mazeMorris water maze
Improved presynaptic functionExcitabilityLTP
Less amyloid plaquescortex hippocampus
Apoptosis was not influenced cleaved caspase-3 stainingFluoroJade staining
Tóth et al. 2013. Cell stress Chaperons 18.(6):759-71
Less neuronal deathFluoroJade staining of cortical and hippocampalslices
Tóth et al. 2010. Cell stress Chaperons 15. (6):807-17
Chronic alcohol consumption (20% ethanol for 5 weeks)
M.E. Tóth, M. Sántha October 19, 2016
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(source: http://omrf.org/about-omrf)
(source: http://www.webmd.com/alzheimers/)
Alzheimer’s disease
(source: https://halcyonorganics.com/)
Azheimer’s disease
M.E. Tóth, M. Sántha October 19, 2016
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(source: http://www.bmb.leeds.ac.uk/staff/nmh/amy.html)
(source:http://scitechdaily.com/)
(source: http://www.emoryhealthsciblog.com/)
M.E. Tóth, M. Sántha October 19, 2016
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X
APPSwexPse1dE9AD model mice
Hsp27 overexpressing
(source: http://sfari.org/news-and-opinion)
AD model X Hsp27 transgenic mice
(sources: http://jaxmice.jax.org/)
Expression of Hsp27 protein in the brain
Tóth et al. 2013. Cell Stress Chaperons 18.(6):759-71
Morris water maze
(source: http://neuroamer.wordpress.com/)
M.E. Tóth, M. Sántha October 19, 2016
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Barnes maze
(source: http://blog.163.com/)
Effect of Hsp27 overexpressionon behavior of AD mice
Tóth et al. 2013. Cell Stress Chaperons 18.(6):759-71
Effect of Hsp27 overexpression on presynaptic plasticity in AD mice
LTP
Neuronal excitability
Paired-pulsefacilitation (PPF)
Tóth et al. 2013. Cell Stress Chaperons 18.(6):759-71
M.E. Tóth, M. Sántha October 19, 2016
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hippocampus
cortex
Effect of Hsp27 overexpression in AD miceon amyloid plaque formation
on neuronal death
Tóth et al. 2013. Cell Stress Chaperons 18.(6):759-71
Thank you for your attention!
This work is supported by the European Union, co-financed by the European Social Fund, within the framework of " Practice-
oriented, student-friendly modernization of the biomedical education for strengthening the international
competitiveness of the rural Hungarian universities " TÁMOP-4.1.1.C-13/1/KONV-2014-0001 project.