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CLINICAL AND RESEARCH MEMORY CENTER LARIBOISIERE HOSPITAL PARIS FRANCE UNIVERSITY OF PARIS DIDEROT INSERM UNIT 942
INVOLVEMENT OF PKR IN ALZHEIMER’S DISEASE
J. HUGON, J. DUMURGIER, F. MOUTON LIGER, P. LAPALUS M. PREVOT, S. INDART, JL LAPLANCHE, C. PAQUET
AD NEUROPATHOLOGY
- SENILE PLAQUES- NEUROFIBRILLARY TANGLES- AMYLOID ANGIOPATHY- NEURONAL AND SYNAPTIC LOSSES- NEUROINFLAMMATION
Aβtau
tau
Amyloid cascade hypothesis Hardy J, D. Selko et al
APP
γ sécretase
β sécretaseα sécretasesαAPP
1-42 or 1-40
TROPHIC SOLUBLE APP FRAGMENTS
DIFFUSE PLAQUES (mainly 1-42)
SENILES PLAQUES ( 1-42 and 1-40)
AMYLOID PRECURSOR PROTEIN
Aβ production : 1-40 (90%) 1-42 (10%) Selko
P3 AICD
sβAPP
Oligomers
pTAU
KINASES
Jack et al 2013
Trinh et al 2009
eiF2α kinases
+ BACE 1
PS1
KINASE PKR: CELLULAR ACTIONS
- PKR is a pro-apoptotic interferon- induced stress S/T Kinase
- PKR is an ubiquitous Kinase present in the cytosol and the nucleus
- PKR is activated by viruses, cytokines, calcium, ER stress, Aβ
- PKR is implicated in inflammation, innate immunity, autophagy
- PKR is activated by autophosphorylation induced by the protein PACT
Adapted from Garcia et al 2007
PKR: apoptosis pathways and inflammation
Inflammation
ATF4
Neurobiol Aging 2012
Hippocampus Fear conditioning
ApoE4 and PKR
Enhanced spatial memory in PKR -/- mice
Mean escape latenciesMorris Water Maze
Cell 2012
MEMORY AND PKR
Chang et al 2002Paquet et al 2008
PKR IN AD BRAINS
Control AD
AD AD
Page et al 2005
Bose et al Brain Pathol 2010
BBA 2012
PRI: PKR inhibitor SH-SY5Y cells
Brain Pathol 2012
PKR
Inflammation ApoptosisChang et al
BACE1/AβMouton Liger
Virus, cytokines, Ca++, Aβ,
Neuronal Death Plaques Tangles
Phospho tauBose et al
Memory
PACT
ApoE4
Paquet et al
Blood testsLymphocytes
Paccalin et al 2006
PKR AS BLOOD BIOMARKER IN AD
Mouton Liger et al Biol Psy. 2012
PKR AS A CSF BIOMARKER
Western blot results
Mouton Liger et al Biol Psy. 2012
Mouton Liger et al Biol Psy. 2012
RESULTS
Increase (300%) of CSF pPKR levels in AD patients
Mouton Liger et al Biol Psy. 2012
ROC CURVES
Mouton Liger et al Biol Psy. 2012
CORRELATIONS pPKR and pTAU
Mouton Liger et al Biol Psy. 2012
CSF pPKR AND COGNITIVE DECLINE
Dumurgier et al 2013
Dumurgier et al 2013
Tertiles of CSF pPKR Levels
AD patients with high CSF pPKR levels decline more rapidly
Low
MediumHigh
Dumurgier et al 2013
MCI Dementia
CSFPKR
Cut off
10 years ?
Evolution of CSF PKR
?
When CSF pPKR levels begin to be abnormal ?
CONCLUSIONS
- Activated PKR is increased in the brain and blood lymphocytes of AD patients
- Activated PKR is increased in the CSF of AD patients and predicts cognitive decline
- Activated PKR is increased in the CSF of MCI patients
- PKR is involved in neuronal pathways linked to AD (Aβ, tau, ApoE4)
- PKR is implicated in the process of inflammation, autophagy and apoptosis
- PKR is involved in the control of memory
- PKR represents a new diagnostic and prognostic biomarker in CSF
- PKR is a new therapeutic target in AD
