Molecular Integration of CNS Neurodegenerative

Dementias

Christine Van Broeckhoven VIB8 - Department of Molecular Genetics

IBB – Laboratory of NeurogeneticsNeurodegenerative Brain Diseases Group

University of AntwerpBelgium

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)

Abnormal Protein Aggregates

NeurodegenerationLewy Bodies

Pick Bodies Nuclear polyglu

inclusions

PrPSc

plaques

Senileplaques

Neurofibrillarytangles

Cerebral ProteopathiesDisease Aggregated

proteinPathological lesion

Proteopathy

AD Amyloid β Amyloid βPlaques

Amyloidosis

Tau Neurofibrillary tangles

Tauopathy

CAA, HCHWA-D

Amyloid β Vasculature Amyloidosis

Pick’s disease

Tau Pick bodies Tauopathy

PD/LBD Synuclein α Lewy bodies/neurites

Synucleinopathy

CJD/GSS Prion Prion plaques Prionopathy

Tau

Amyloid β

Synuclein α

CAA

LBD PD

A Spectrum of Neurodegenerative Disorders

?

Alzheimer’sdisease

CongophilicAmyloidAngiopathy

Frontotemporaldementia

Amyloid Tau

Parkinson’sdisease

Alzheimer’sdisease

DiffuseLewy bodydisease

Lewy bodydementia

SCNA Tau

Multifactorial Diseases

Nu

mb

er

of

pati

en

ts

genetic environmentgenetic +environment

moleculargenetics

geneticepidemiology

epidemiology

Genetic

Environment

Early-onset

Late-onset

Autosomal Dominant Dementias

Disease Linkage

Gene Mutations

Early-onset AD

Ch 21Ch 14Ch 1

APPPS 1PS 2

Clustered missense/duplicationMainly missenseMainly missense

CJD/GSS Ch 20 PRNP Mainly missense/insertions

PD Ch 4Ch12Ch 6Ch1

SNCALRRK2ParkinDJ-1

Missense and dosageMissenseMissense and dup/delMissense and del/dup

FTD Ch 17 MAPT Missense and splicingHD Ch 4 HD Expanded

polyglutamine stretch

Prote(in)opathy cascade

protein misfolded protein

mutation

aggregation

deposition

Neurodegeneration

beta-sheet

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

Alzheimer’s dementia The Paradigm Proteopathy

Plaque

Tangle

Tangle

Silver stain Congo red stain

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

Gandy, J Clin Invest, 2005

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

APP Duplication in ADGenomic APP tandem duplication

(Rovelet-Lecrux et al., 2006)

– 5/65 autosomal dominant AD families (~ 8 %)

– 5 different breakpoints– APP and several surrounding genes

Dutch APP Duplication Family

Interphase FISH

FISH of mechanically stretched ch21

Reference probe Ch 21

APP probe

Trisomy 21

1104 1104

58

1/10 Dutch AD families = 10 %Sleegers et al. Brain 2006

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

Amyloid Cascade Revisited

Aβ42/Aβ40

APP missense mutations PS missense mutations

PS1 promoter variations

APP promoter variations

APP locus duplicationAPP triplication in Down Syndrome

APP

AD

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%

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

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

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, ?)

Novel PS1 G183V in classical Picks’ disease

Dermaut et al. Ann Neurol 2004

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

Dermaut et al. TIG 2005

Overlapping Proteopathies

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