1 / 27

CLINICAL AND RESEARCH MEMORY CENTER LARIBOISIERE HOSPITAL PARIS FRANCE

INVOLVEMENT OF PKR IN ALZHEIMER’S DISEASE. J. HUGON, J. DUMURGIER, F. MOUTON LIGER, P. LAPALUS M. PREVOT, S. INDART, JL LAPLANCHE, C. PAQUET. CLINICAL AND RESEARCH MEMORY CENTER LARIBOISIERE HOSPITAL PARIS FRANCE UNIVERSITY OF PARIS DIDEROT

aburnell
Download Presentation

CLINICAL AND RESEARCH MEMORY CENTER LARIBOISIERE HOSPITAL PARIS FRANCE

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. INVOLVEMENT OF PKR IN ALZHEIMER’S DISEASE J. HUGON, J. DUMURGIER, F. MOUTON LIGER, P. LAPALUS M. PREVOT, S. INDART, JL LAPLANCHE, C. PAQUET CLINICAL AND RESEARCH MEMORY CENTER LARIBOISIERE HOSPITAL PARIS FRANCE UNIVERSITY OF PARIS DIDEROT INSERM UNIT 942

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

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

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

  5. Jack et al 2013

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

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

  9. Hippocampus Fear conditioning Neurobiol Aging 2012 ApoE4 and PKR

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

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

  12. Bose et al Brain Pathol 2010

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

  14. Brain Pathol 2012

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

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

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

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

  19. 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

  24. Dumurgier et al 2013

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

  26. Evolution of CSF PKR CSF PKR ? Cut off 10 years ? MCI Dementia 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

More Related