1. 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

2. AD NEUROPATHOLOGY - SENILE PLAQUES - NEUROFIBRILLARY TANGLES - AMYLOID ANGIOPATHY - NEURONAL AND SYNAPTIC LOSSES - NEUROINFLAMMATION AβAβ tau

3. Amyloid cascade hypothesis Hardy J, D. Selko et al

4. APP γ sécretase β sécretase α sécretase sαAPP 1-42 or 1-40 TROPHIC SOLUBLE APP FRAGMENTS DIFFUSE PLAQUES (mainly 1-42) SENILES PLAQUES ( 1-42 and 1-40) AMYLOID PRECURSOR PROTEIN A β production : 1-40 (90%) 1-42 (10%) Selko P3 AICD sβAPP Oligomers pTAU KINASES

5. Jack et al 2013

6. Trinh et al 2009 eiF2α kinases + BACE 1 PS1

7. 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

8. Adapted from Garcia et al 2007 PKR: apoptosis pathways and inflammation Inflammation ATF4

9. Neurobiol Aging 2012 Hippocampus Fear conditioning ApoE4 and PKR

10. Enhanced spatial memory in PKR -/- mice Mean escape latencies Morris Water Maze Cell 2012 MEMORY AND PKR

11. Chang et al 2002 Paquet et al 2008 PKR IN AD BRAINS ControlAD Page et al 2005

12. Bose et al Brain Pathol 2010

13. BBA 2012 PRI: PKR inhibitor SH-SY5Y cells

14. Brain Pathol 2012

15. PKR Inflammation Apoptosis Chang et al BACE1/Aβ Mouton Liger Virus, cytokines, Ca++, A β, Neuronal DeathPlaquesTangles Phospho tau Bose et al Memory PACT ApoE4 Paquet et al

16. Blood tests Lymphocytes Paccalin et al 2006 PKR AS BLOOD BIOMARKER IN AD

17. Mouton Liger et al Biol Psy. 2012 PKR AS A CSF BIOMARKER

18. Western blot results Mouton Liger et al Biol Psy. 2012

20. RESULTS Increase (300%) of CSF pPKR levels in AD patients Mouton Liger et al Biol Psy. 2012

21. ROC CURVES Mouton Liger et al Biol Psy. 2012

22. CORRELATIONS pPKR and pTAU Mouton Liger et al Biol Psy. 2012

23. CSF pPKR AND COGNITIVE DECLINE Dumurgier et al 2013

25. Tertiles of CSF pPKR Levels AD patients with high CSF pPKR levels decline more rapidly Low Medium High Dumurgier et al 2013

26. MCIDementia CSF PKR Cut off 10 years ? Evolution of CSF PKR ? When CSF pPKR levels begin to be abnormal ?

27. 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