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

1. Deciphering the
mechanism
underlying
late-onset
Alzheimer Disease
Irene Knuesel, PhD
Institute of Pharmacology and Toxicology
University of Zurich
Alzforum Webinar 12.12.2012
anti-Ab/DAPI
anti-Ab/FluoroJ/DAPI

2. 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

3. 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
compartments
Low-grade but chronic, cellular stress: • Significant increase in APP levels
Accelerated cell/brain aging? • Increase in proteolytic APP fragments
PolyIC = polyriboinosinic:polyribocytidylic acid; viral mimic Meyer et al., 2006; Krstic et al., 2012

4. 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

5. PolyI:C Model of AD in wt Mice: pTau
Krstic et al., 2012

6. PolyI:C Model of AD in wt Mice: APP
Krstic et al., 2012

7. PolyI:C Model of AD in wt Mice: APP
Krstic et al., 2012

8. 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

9. Inflammation-induced Amyloid Plaques
Krstic et al., 2012

10. Accumulation of APP Fragments
N-APP 3xTgAD
APP
Ab 1-40/42 PolyIC N-APP
3xTgAD AD patient, 88y
Ab
Dapi AbPolyIC
1-40/42 Hippocampus CA1
Dapi Dapi
Krstic et al., 2012

11. Amyloid-b and Tau Pathology
pTauS422
N-APP
Dapi
Phosphorylated Neurofilament
Aged Rhesus Monkey (34 y)
3xTgAD
PolyIC Walker and Cork, 1999
Alzheimer’s Disease, 2nd Edition
unpublished

12. From PolyI:C model to AD pathogenesis?
DAPI/N-APP DAPI/pTau
Aged wt double-hit PolyI:C mice
Aged tg AD PolyI:C mice
Late-onset AD patients
Krstic et al., 2012 and unpublished pictures

13. Sequence of neuropathological events
Krstic and Knuesel, Nature Rev Neurology, 2012

14. Step 1
15 months
9 months
NaCl mouse mouse
NaCl
CA1 CA1
MBP Axon
15 months
PolyI:C mice
Doehner et al,
2012, EJN

15. Step 2
15 month-old
PolyI:C mice
Fiala et al, 2007, Brain Struct Funct
Aged Rhesus Monkeys

16. 15 month-old
PolyI: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

17. 15 month-old
PolyI: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

18. 15 month-old
PolyI: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

19. Step 6
15 month-old
PolyI:C mice
Auguste D. (Alois Alzheimer's 1907)
Cerebral cortex, Bielschowsky's silver impregnation
Zeiss MIRAX scanned original tissue section
©Zeiss & M. Graeber (http://www.zeiss.de/alzheimer)

20. Age- and disease-dependent
gene 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
modulators
Disease Progression Model by Podtelezhnikov and Colleagues
Based on transcriptional profiling (>600 brains)
Podtelezhnikov et al., PLosOne, 2011

21. 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 Forschung
Collaborations 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