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 Neurodegeneration Lewy Bodies Pick Bodies Nuclear polyglu inclusions PrP Sc plaques Senile plaques Neurofibrillary tangles

4. Cerebral Proteopathies DiseaseAggregated protein Pathological lesion Proteopathy ADAmyloid β Plaques Amyloidosis TauNeurofibrillary tangles Tauopathy CAA, HCHWA-D Amyloid βVasculatureAmyloidosis Pick’s diseaseTauPick bodiesTauopathy PD/LBDSynuclein αLewy bodies/neurites Synucleinopathy CJD/GSSPrionPrion plaquesPrionopathy

5. Tau Amyloid β Synuclein α CAA LBD PD

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

7. Multifactorial Diseases Number of patients genetic environment genetic + environment molecular genetics genetic epidemiology GeneticEnvironment Early-onsetLate-onset

8. Autosomal Dominant Dementias DiseaseLinkageGeneMutations Early-onset AD Ch 21 Ch 14 Ch 1 APP PS 1 PS 2 Clustered missense/duplication Mainly missense CJD/GSS Ch 20PRNP Mainly missense/insertions PD Ch 4 Ch12 Ch 6 Ch1 SNCA LRRK2 Parkin DJ-1 Missense and dosage Missense Missense and dup/del Missense and del/dup FTD Ch 17MAPTMissense and splicing HD Ch 4HD Expanded polyglutamine stretch

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

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 Plaque Tangle Silver stainCongo 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. Dutch APP Duplication Family Interphase FISH FISH of mechanically stretched ch21 Reference probe Ch 21 APP probe Trisomy 21 1104 58 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. Amyloid Cascade Revisited Aβ42/ Aβ40  APP missense mutations PS missense mutationsPS1 promoter variationsAPP promoter variationsAPP locus duplicationAPP triplication in Down Syndrome APP AD

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

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 shapedGlobular shaped Pirici, Kumar-Singh et al JNEN 2006

25. Dermaut et al. TIG 2005 Overlapping Proteopathies

26. Acknowledgements 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 Christine Van Broeckhoven