Molecular Integration of CNS Neurodegenerative Dementias

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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

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Neurodegenerative Brain Diseases

• Alzheimers Disease (AD)
• Vascular Dementia (VaD)
• Lewy Body Dementia (LBD)- Parkinsons Disease
  (PD) with Dementia
• Frontotemporal Dementia (FTD)
• Others e. g. Creutzfeldt-Jakob disease (CJD),
  Huntingtons disease (HD)

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Abnormal Protein Aggregates
Neurofibrillary tangles
Senile plaques
Lewy Bodies
PrPSc plaques
Neurodegeneration
Pick Bodies
Nuclear polyglu inclusions
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Cerebral Proteopathies
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Synuclein a
PD
LBD
Tau
Amyloid ß
CAA
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A Spectrum of Neurodegenerative Disorders ?
Amyloid
Tau
Alzheimers disease
Congophilic Amyloid Angiopathy
Frontotemporal dementia
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Multifactorial Diseases
molecular genetics
genetic epidemiology
epidemiology
Number of patients
environment
genetic
genetic environment
Genetic
Environment
Early-onset
Late-onset
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Autosomal Dominant Dementias
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Prote(in)opathy cascade
mutation
beta-sheet
aggregation
protein
misfolded protein
deposition
Neurodegeneration
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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

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Alzheimers dementia The Paradigm Proteopathy
Tangle
Plaque
Tangle
Silver stain
Congo red stain
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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

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Gandy, J Clin Invest, 2005
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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 PSs are distributed over the
  protein
• Mutations affect APP processing
• Increased ratio of Aß42/Aß40

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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

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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
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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
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Amyloid Cascade Revisited
AD
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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
18 22
26 48
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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

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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

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AD FTD spectrum

• Alzheimers 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, ?)

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Novel PS1 G183V in classical Picks disease
Dermaut et al. Ann Neurol 2004
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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
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Overlapping Proteopathies
Dermaut et al. TIG 2005
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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
• Kristl Vennekens
• Ivy Cuyt
• Sally Serneels
• Kenan Kamali
• Research nurses
• Karin Peeters
• Mie Mattheijssens

Christine Van Broeckhoven