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