Deciphering the mechanism underlying late-onset

Alzheimer Disease

Irene Knuesel, PhDInstitute of Pharmacology and Toxicology

University of ZurichAlzforum Webinar 12.12.2012

anti-Ab/FluoroJ/DAPIanti-Ab/DAPI

Autosomal dominant mutations

Age Genetic risk factors

Environmental risk factors (worldwide prevalence in %)

Midlife Obesity (3.4%) Diabetes (6.4%) Midlife Hypertension (8.9%) Depression (13.2%) Physical inactivity (17.7%) Smoking (27.4%) Low education (40%)

Approaches in Basic Research

Barnes and Yaffe, Lancet Neurology, 2011

CHRONICCELLULAR STRESS

aging models of AD (<5%)

transgenic AD models (>95%)~1-5 % of patients

Early-Onset AD

~95-99 % of patientsLate-Onset AD

Modeling cellular stress in vivothrough chronic inflammation

Meyer et al., 2006; Krstic et al., 2012

Maternal und fetal cytokines

PolyIC = polyriboinosinic:polyribocytidylic acid; viral mimic

Low-grade but chronic, cellular stress:Accelerated cell/brain aging?

SynaptogenesisGlutamatergic system

NeurogenesisCognitive impairments

Chronic increase in cytokine levels

At 15 months: PolyI:C versus NaCl offspring

• Significant increase in Tau phosphorylation• Translocation from axonal to somatodendritic compartments

• Significant increase in APP levels• Increase in proteolytic APP fragments

5 mg/kg PolyI:C or NaCl

12 months old PolyI:C or NaCl mouse

“Second hit”

15 months: Tissue collection & processing

NeuroinflammationpTau

APP processing

PolyI:C Model of Alzheimer’s Dementia

Krstic et al., 2012

PolyI:C Model of AD in wt Mice: pTau

Krstic et al., 2012

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

Chronic Inflammation in tgAD Mice

5 mg/kg PolyI:C or NaCl

3xtg-AD, 4 months old

15 months: Tissue collection & processing

APP processingpTau

Inflammation-induced Amyloid Plaques

Krstic et al., 2012

Accumulation of APP Fragments

APPAbDapi

3xTgADPolyIC

N-APPAb1-40/42

Dapi

AD patient, 88yHippocampus CA1

N-APPAb1-40/42

Dapi

3xTgADPolyIC

Krstic et al., 2012

Amyloid-b and Tau Pathology

3xTgADPolyIC

pTauS422N-APPDapi

Phosphorylated Neurofilament Aged Rhesus Monkey (34 y)

Walker and Cork, 1999Alzheimer’s Disease, 2nd Edition

unpublished

From PolyI:C model to AD pathogenesis?

Aged wt double-hit PolyI:C miceDAPI/pTauDAPI/N-APP

Late-onset AD patients

Aged tg AD PolyI:C mice

Krstic et al., 2012 and unpublished pictures

Sequence of neuropathological events

Krstic and Knuesel, Nature Rev Neurology, 2012

Step 1

15 monthsPolyI:C mice

Doehner et al, 2012, EJN

ReelinMBP

15 monthsNaCl mouseCA1

ReelinAxon

9 monthsNaCl mouseCA1

Step 2

15 month-oldPolyI:C mice

Fiala et al, 2007, Brain Struct FunctAged Rhesus Monkeys

Step 3

15 month-oldPolyI:C mice

APP-IR Rat TBI model

a) Gorazd et al, 2005, Scienceb) Stone et al., 2001, Exp Neurol

tg AD mice

b)

a)

ChAT fibers

Step 4

15 month-oldPolyI:C mice

Xiao et al. 2011, Neurosci BullPostmortem brain slices

AD patients

pTau

APP/Ab

Microinjection of biotinylated dextran amine (BDA) in M-ACSF

Step 5

15 month-oldPolyI:C mice

c-e) Nixon & Yang 2011, Neurobiol Dis d) Nixon et al. 2005, J Neuropathol Exp Neurol

f) Krstic et al. 2012, J NeuroinflammationHuman AD patients

g) Walker & Cork, 1999, Alzheimer’s Disease 2nd ed

CatD

CatD

autophagicvacuoles rhesus monkey 34 y

g) Cytochrome Coxidase

Step 6

15 month-oldPolyI:C mice

©Zeiss & M. Graeber (http://www.zeiss.de/alzheimer)

Auguste D. (Alois Alzheimer's 1907)Cerebral cortex, Bielschowsky's silver impregnationZeiss MIRAX scanned original tissue section

Age- and disease-dependent gene expression patterns: ND vs AD

Podtelezhnikov et al., PLosOne, 2011

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

modulators

Disease Progression Model by Podtelezhnikov and Colleagues

Based on transcriptional profiling (>600 brains)

AcknowledgementsResearch Team

Dimitrije Krstic

Tina Notter

Sandra Pfister

Tamara Weber

Maya Barben

Felicitas Gilgen

Susanne Münzing

Ricardo Koch

Tilo Gschwind

Conny Schwerdel

Former members

Jana Doehner

Amrita Madhusudan

Myriam Rodriguez

Prisca Vogel

Claudine Imhof

Samira Kocherhans

Martina Hilfiker

Abigail Manalastas

Karin Breu

Financial support

Stiftung für medizinisch-biologische Forschung

Collaborations ETHZ/UZH

Roger Nitsch, MD

Manuela Neumann, MD

Urs Meyer, PhD

International Collaborations

Tony Wyss-Coray, PhD, Stanford

Frank Heppner, MD, Charité Berlin

Joachim Herz, MD, UT Southwestern

Edwin Weeber, PhD, USF

Olga Meyenfisch Stiftung

Hartmann Müller Stiftung