Molecular Integration of CNS Neurodegenerative Dementias

1. Molecular Integration of CNS Neurodegenerative Dementias Christine Van Broeckhoven VIB8 - Department of Molecular Genetics IBB – Laboratory of Neurogenetics Neurodegenerative Brain Diseases Group University of Antwerp Belgium

2. Neurodegenerative Brain Diseases • Alzheimer’s Disease (AD) • Vascular Dementia (VaD) • Lewy Body Dementia (LBD)- Parkinson’s Disease (PD) with Dementia • Frontotemporal Dementia (FTD) • Others e. g. Creutzfeldt-Jakob disease (CJD), Huntington’s disease (HD)

3. Abnormal Protein Aggregates Neurofibrillary tangles Senile plaques Lewy Bodies PrPSc plaques Neurodegeneration Pick Bodies Nuclear polyglu inclusions

4. Cerebral Proteopathies

5. Synuclein α PD LBD Tau Amyloid β CAA

6. Tau SCNA Parkinson’s disease Diffuse Lewy body disease Lewy body dementia Alzheimer’s disease A Spectrum of Neurodegenerative Disorders ? Amyloid Tau Congophilic Amyloid Angiopathy Alzheimer’s disease Frontotemporal dementia

7. Multifactorial Diseases molecular genetics genetic epidemiology epidemiology Number of patients environment genetic genetic + environment Genetic Environment Early-onset Late-onset

8. Autosomal Dominant Dementias

9. Prote(in)opathy cascade mutation beta-sheet aggregation protein misfolded protein deposition Neurodegeneration

10. Cerebral Prote(in)opathies • Disorders are clinically and genetically heterogeneous • Biochemical level: Abnormal conformation and assembly of proteins • Increasing understanding of the process whereby proteins self-assemble and injure tissues • But the fundamental origin still remains largely unknown

11. Alzheimer’s dementia The Paradigm Proteopathy Tangle Plaque Tangle Silver stain Congo red stain

12. Genetics of AD • Early-onset AD : ~ 1% • Positive family history in 60%, of which 10% with autosomal dominant inheritance • Mutations in APP, PS1 and PS2 • Overall 5% • Familial 10% • Autosomal dominant 20% • Classical Alzheimer pathology • Amyloid plaques and tau tangles • APOE4 increases risk for AD, and decreases onset age

13. Gandy, J Clin Invest, 2005

14. Mutations in AD • Majority of the mutations are missense mutations • Most mutations are in PS1 (78%) • Mutations in APP are located at secretase cleavage sites • Mutations in PS’s are distributed over the protein • Mutations affect APP processing Increased ratio of Aβ42/Aβ40

15. APP Duplication in AD Genomic APP tandem duplication (Rovelet-Lecrux et al., 2006) • 5/65 autosomal dominant AD families (~ 8 %) • 5 different breakpoints • APP and several surrounding genes

16. 58 Dutch APP Duplication Family Interphase FISH Trisomy 21 APP probe Reference probe Ch 21 1104 1104 FISH of mechanically stretched ch21 1/10 Dutch AD families = 10 % Sleegers et al. Brain 2006

17. APP promoter mutations • Genetic variants that increase APP expression • Level of APP expression influences onset age • APP promoter mutations increasing levels by near 2-fold, like in APP duplications, mimic inherited forms of AD Theuns et al. AJHG 2006

18. PS missense mutations APP missense mutations PS1 promoter variations APP promoter variations APP locus duplication APP Aβ42/ Aβ40 APP triplication in Down Syndrome Amyloid Cascade Revisited AD

19. Pathology of FTD • Frontal and anterio-temporale cortex atrophy • Neuronal loss, gliosis, spongiosis • Histopathology FTD FTD with ubiquitin positive inclusions = FTDU FTD lacking distinctive histopathology = DLDH Tau positive FTD (Pick bodies – NFT) = tauopathy 36% – 50% 26% – 48% 18% – 22%

20. Genetics of FTD • Familial FTD: 38 – 50%, majority autosomal dominant • 3 loci: ch 17, ch 3, ch 9 • Microtubule Associated Protein Tau • MAPT • 17q21 • 10 – 43% familial FTD • tau-positive inclusions • Majority has no tauopathy and no MAPT mutation

21. MAPT mutations in FTDP-17 • Missense mutations: • in exon 1, 9, 10, 12 and 13 • mainly affecting microtubule binding domains • Splice site mutations: • in intron 3’ of exon 10 • enhances exon 10 splicing • results in abnormal preponderance of 4- over 3-repeat tau

22. AD – FTD spectrum • Alzheimer’s disease • Amyloid Precursor Protein (APP) • Presenilin 1 (PS1) • Presenilin 2 (PS2) • Apolipoprotein E (APOE) • Prion Protein (PRNP) • Microtubule Associated Protein Tau (MAPT) • Frontotemporal dementia • Microtubule Associated Protein Tau (MAPT) • Presenilin 1 (PSEN1) • FTDU (VCP, ?)

23. Novel PS1 G183V in classical Picks’ disease Dermaut et al. Ann Neurol 2004

24. Tau-negative, Ubiquitin-positive Frontotemporal Dementia Chromosome 17q21 linked FTDU without MAPT mutations or FTDU-17 Cat-eye shaped Globular shaped Pirici, Kumar-Singh et al JNEN 2006

25. Overlapping Proteopathies Dermaut et al. TIG 2005

26. Scientists Marc Cruts Samir Kumar-Singh Jessie Theuns Roos Rademakers Kristel Sleegers Veerle Bogaerts Bianca Van Broeck Julie van der Zee Daniel Pirici Ilse Gijselinck Nathalie Brouwers Hans Wils Karen Nuytemans Technicians Marleen Van den Broeck Ellen Corsmit Tim De Pooter Krist’l Vennekens Ivy Cuyt Sally Serneels Kenan Kamali Research nurses Karin Peeters Mie Mattheijssens Acknowledgements Christine Van Broeckhoven