Kneusel - Neuroinflammation
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Kneusel - Neuroinflammation

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Presentation madeby Irene Kneusel, PhD, at the December 12, 2012 webinar hosted by the Alzheimer Research Forum. http://www.alzforum.org/res/for/journal/detail.asp?liveID=207

Presentation madeby Irene Kneusel, PhD, at the December 12, 2012 webinar hosted by the Alzheimer Research Forum. http://www.alzforum.org/res/for/journal/detail.asp?liveID=207

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  • Klinik: infektionen – AuslösereinerDemenz
  • Modified artifical CSF, staining with ABC kit and DAB staining

Kneusel - Neuroinflammation Kneusel - Neuroinflammation Presentation Transcript

  • Deciphering the mechanism underlying late-onset Alzheimer Disease Irene Knuesel, PhDInstitute of Pharmacology and Toxicology University of Zurich Alzforum Webinar 12.12.2012 anti-Ab/DAPI anti-Ab/FluoroJ/DAPI
  • Approaches in Basic Research ~1-5 % of patients Autosomal dominant mutations transgenic AD models (>95%) Early-Onset AD Age aging models of AD (<5%) Genetic risk factors Environmental risk factors (worldwide prevalence in %)  Midlife Obesity (3.4%)  Diabetes (6.4%)  Midlife Hypertension (8.9%) CHRONIC  Depression (13.2%) CELLULAR STRESS  Physical inactivity (17.7%)  Smoking (27.4%)  Low education (40%) ~95-99 % of patients Barnes and Yaffe, Lancet Neurology, 2011 Late-Onset AD
  • Modeling cellular stress in vivo through chronic inflammation Maternal und fetal cytokines Synaptogenesis Glutamatergic system At 15 months: PolyI:C versus NaCl offspring Neurogenesis • Significant increase in Tau phosphorylation Cognitive impairments • Translocation from axonal to somatodendritic Chronic increase in cytokine levels compartmentsLow-grade but chronic, cellular stress: • Significant increase in APP levels Accelerated cell/brain aging? • Increase in proteolytic APP fragmentsPolyIC = polyriboinosinic:polyribocytidylic acid; viral mimic Meyer et al., 2006; Krstic et al., 2012
  • PolyI:C Model of Alzheimer’s Dementia 5 mg/kg PolyI:C or NaCl 12 months old PolyI:C or NaCl mouse “Second hit” 15 months: Tissue collection & processing Neuroinflammation pTau APP processing Krstic et al., 2012
  • PolyI:C Model of AD in wt Mice: pTau Krstic et al., 2012
  • PolyI:C Model of AD in wt Mice: APP Krstic et al., 2012
  • PolyI:C Model of AD in wt Mice: APP Krstic et al., 2012
  • Chronic Inflammation in tgAD Mice 5 mg/kg PolyI:C or NaCl 3xtg-AD, 4 months old 15 months: Tissue collection & processing APP processing pTau
  • Inflammation-induced Amyloid Plaques Krstic et al., 2012
  • Accumulation of APP FragmentsN-APP 3xTgAD APPAb 1-40/42 PolyIC N-APP 3xTgAD AD patient, 88y AbDapi AbPolyIC 1-40/42 Hippocampus CA1 Dapi Dapi Krstic et al., 2012
  • Amyloid-b and Tau PathologypTauS422N-APPDapi Phosphorylated Neurofilament Aged Rhesus Monkey (34 y)3xTgADPolyIC Walker and Cork, 1999 Alzheimer’s Disease, 2nd Editionunpublished
  • From PolyI:C model to AD pathogenesis? DAPI/N-APP DAPI/pTauAged wt double-hit PolyI:C mice Aged tg AD PolyI:C mice Late-onset AD patients Krstic et al., 2012 and unpublished pictures
  • Sequence of neuropathological events Krstic and Knuesel, Nature Rev Neurology, 2012
  • Step 115 months 9 monthsNaCl mouse mouse NaClCA1 CA1 MBP Axon 15 months PolyI:C miceDoehner et al, 2012, EJN
  • Step 2 15 month-old PolyI:C miceFiala et al, 2007, Brain Struct Funct Aged Rhesus Monkeys
  • 15 month-oldPolyI:C mice Step 3 a) ChAT fibers b) APP-IR Rat TBI model a) Gorazd et al, 2005, Science b) Stone et al., 2001, Exp Neurol tg AD mice
  • 15 month-oldPolyI:C mice Step 4 Microinjection of biotinylated dextran amine (BDA) in M-ACSF pTau APP/Ab Xiao et al. 2011, Neurosci Bull Postmortem brain slices AD patients
  • 15 month-oldPolyI:C mice Step 5 CatD g) Cytochrome C CatD oxidase autophagic vacuoles rhesus monkey 34 y c-e) Nixon & Yang 2011, Neurobiol Dis d) Nixon et al. 2005, J Neuropathol Exp Neurol f) Krstic et al. 2012, J Neuroinflammation Human AD patients g) Walker & Cork, 1999, Alzheimer’s Disease 2nd ed
  • Step 6 15 month-old PolyI:C miceAuguste D. (Alois Alzheimers 1907)Cerebral cortex, Bielschowskys silver impregnationZeiss MIRAX scanned original tissue section ©Zeiss & M. Graeber (http://www.zeiss.de/alzheimer)
  • Age- and disease-dependentgene expression patterns: ND vs AD Genetic risk factors of late-onset AD (GWAS)  APOE e4  PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1, CD33, CLU, CD2AP and CR1, PPP1R3B, TREM2 • lipid metabolism, immune modulators, synaptic modulatorsDisease Progression Model by Podtelezhnikov and ColleaguesBased on transcriptional profiling (>600 brains) Podtelezhnikov et al., PLosOne, 2011
  • Acknowledgements Research Team Former members Financial support Dimitrije Krstic Jana Doehner Tina Notter Amrita Madhusudan Sandra Pfister Myriam Rodriguez Tamara Weber Prisca Vogel Hartmann Müller Stiftung Maya Barben Claudine Imhof Felicitas Gilgen Samira Kocherhans Susanne Münzing Martina Hilfiker Olga Meyenfisch Stiftung Ricardo Koch Abigail Manalastas Tilo Gschwind Karin Breu Conny Schwerdel International Collaborations Stiftung für medizinisch-biologische ForschungCollaborations ETHZ/UZH Tony Wyss-Coray, PhD, Stanford Roger Nitsch, MD Frank Heppner, MD, Charité Berlin Manuela Neumann, MD Joachim Herz, MD, UT Southwestern Urs Meyer, PhD Edwin Weeber, PhD, USF