Loosening the G Loosening the G Gordian Knot: Gordian Knot: Unraveling Alzheimer D Disease Biology and Finding The Finding The erapeutic erapeutic Targets Using Gene Gene etic etic Approa aches Lindsay A. y Farrer, Ph.D . , Division of Bio omedical Genetics Boston University y School of Medicine y No Di isclosures 1
ALZHEIMER ALZHEIMER R DISEASE R DISEASE Progressive loss of me emory and cognition Onset in most cases aft Onset in most cases aft fter age 65 years fter age 65 years, but can occur as early as age 30 No effective treatment t or cure
DIAGNO OSIS OF ALZHEIMER R DISEASE Pathologic confirmatio on (“Gold Standard”) Neuropsychological an nd brain imaging tests Rule out other organic Rule out other organic causes (e g stroke) causes (e.g., stroke) Progression for at least i f l t one year
NEUROPATH HOLOGY OF ALZHEIMER R DISEASE $ -amyloid deposition n in L parenchymal seni ile plaques L cerebral blood ve essel walls Neurofibrillary tangle y g es in neurons of cerebral cortex and d hippocampus
Neuropathology of Neuropathology of Alzheimer Disease Alzheimer Disease
Alzheimer Disease is a Public Health Menace Affects 13% of people e >age 65; 43% ages 85+ 7 th leading cause of de eath in US (5 th among >65) More than 5.4 million Americans afflicted AD patients fill more t than 50% of all nursing home beds and consum me an estimated $172 billion per year in hea alth care resources
Established Gene Loci for Alzheimer Disease Deterministic Mutations: Amyloid Precurser Protein (APP) Presenilin-1 (PS-1) Presenilin 2 (PS 2) Presenilin-2 (PS-2) Susceptibility Polymorphism: Susceptibility Polymorphism: Apolipoprotein E (APOE)
Sisodia et al 2001; 24(11):S2-6
Gene Defects C Causing Autosomal Dominant Alz D i t Al zheimer Disease h i Di Numbe er Onset Age Relative Gene Gene Chromosome Chromosome of Mutat of Mutat tions tions (Range) (Range) Frequency* Frequency* APP A 21 21 33 33 3 37 – 65 6 5% % PS1 14 185 29 – 60 70% PS2 1 13 40 – 82 5% – 10% ? ? ? ? 15% – 20% * These effects account for <<1% of all AD cases
Established Gene Loci for Alzheimer Disease Deterministic Mutations: Amyloid Precurser Protein (APP) Presenilin-1 (PS-1) Presenilin 2 (PS 2) Presenilin-2 (PS-2) Susceptibility Polymorphism: Susceptibility Polymorphism: Apolipoprotein E (APOE)
APOLIPOPROTE EIN E (APOE) Plasma protein involved in choles p sterol transport p Produced in liver and in astrocyte es in central and peripheral nervous system Encoded by gene on chromosome e 19 3 alleles ( 2, 3, and 4) resulting g from amino acid substitutions at positions 112 or 158 2, 4 associated with hyperlipide 2 4 associated with hyperlipide emia, type III hyperlipoproteinemia emia type III hyperlipoproteinemia and hypertriglyceridemia (decreas sed binding to lipoprotein receptors)
Myers et al, Neurology 1996; 46:673-677 Myers et al, Neurology 1996; 46:673 677
Odds of Alzheim mer Disease by APOE and Age g in Caucasians Farrer et al. JAMA 1997; 278:1349-1356
Relative Odds of Alzheim mer’s Disease by APOE Genotypes, Age and yp , g d Sex in Caucasians Farrer et al. JAMA 1997; 278:1349-1356
Association Studies in Alzheimer Disease (1995 (1995 -2006) 2006) • By early 2007, 968 association B l 2007 968 i ti n studies in 398 candidate t di i 398 did t genes reported on AlzGene (http://www.alzforum.org/res/ /com/gen/alzgene • None other than APOE with ro obust confirmation • Reasons include: • Initial results false positive • Lack of power in replication s • Lack of power in replication s studies (false negatives) studies (false negatives) • Locus heterogeneity • Clinical heterogeneity • Lack of informative markers • Intralocus (non-allelic) hetero geneity
Mutations Causing Alz zheimer Disease cause mis-process mis-process sing of APP sing of APP Citron et al. Nature Med. 3: 67-72, 1997 APP APOE 4 PS1/PS2 mutations mutations A -secretase -secretase ↓ Uptake, chaperoning, & X degradation of A β AICD AICD (?Signalling) Extracellular TM domain Intracellular APP -secretase t A aggregates A accumulates into neurotoxic oligomers protofibrils
APP is cleaved at s sites which require subcellular traf fficking of APP g PPs α APP APP APP ADAM10/17 BACE1 BACE1 PS1 PS1 Cell surface γ -sec γ -sec BACE1 BACE1 APP APP Endosome Golgi BACE1 AICD APP APP APP BACE1 BACE1 APPs β PS1 Recycling Late A β γ -sec Endosome Endosome APP APP RC Endoplasmic Reticulum
Generation of A β req quires trafficking into selected subcellul lar compartments Late endosomal pathways Cell Surface APPs α ADAM10/17 APP BACE1 APPs β A β PS1 AICD APP-CTF β APP-CTF α APP CTF α Sorting switch APP APP RC VPS26 VPS35 VPS35 Recycling Recycling ER- Endosomes Golgi Secretory Rogaeva et al, Nature Genetics 39 :168-177, 2007 Pathway
Study D Study D Design Design Retromer Retromer complex: complex: VPS26 (10q21) VPS26 (10q21) VPS35 (16q12). VPS35 (16q12). Candidate G Genes In 2 SNPs/gene in VPS10 VPS10- -containing containing Retromer Pathway 2 family cohorts: sorting receptors: sorting receptors: N North European: 124 th E 124 SORT1 (1p21 SORT1 (1p21- -p13) p13) Hispanic: 228 SORCS1 (10q23 SORCS1 (10q23- -q25) q25) Gene(s) associ iated with AD SORCS3 (10q23- SORCS3 (10q23 -q25) q25) SORCS2 (4p16) SORCS2 (4p16) SORL1 (11q23- SORL1 (11q23 -q24) q24) More S SNPs Replicate in Functional Assays independent datasets 4 independent cohorts: 3 independent cohorts: North European case-controls: 178/142 MIRAGE Caucasian: 276 Mayo Clinic Mayo Clinic MIRAGE African American: 238 Israeli-Arab: 111/114
1 250 500 750 1000 1250 1500 1750 2000 2214 Amino Acid #s VPS10 Domains YWT D EG F L DL a F N3 T M SNPS 20 20 1 15 rs3824966 24 rs4935774 8 r rs2276346 rs2282649 19 21 26 2 11 rs668387 14 16 25 7 2070045 -18 Ex26 rs1784933 rs578506 rs4935775 rs11600231 T833T rs1010159 9 22 27 rs12364988 3 3 12 12 17 17 rs689021 rs1699102 rs1614735 5 rs582446 rs12285364 rs556349 29 23 rs11218304 10 13 18 rs1131497 rs3824968 4 6 rs641120 28 rs2298813 rs11218340 rs661057 rs560573 rs1133174 3’ 5’ SO RL 1 L O C283155 L O C399959 (177.43 Kb) 120.68 120.84 121.00 121.16 121.32 121.48 Rogaeva et al, Nature Genetics 39 :168-177, 2007 LOC390256 SC5DL
Ethnic = Hispanic = Arab = Caucasian = Afro-American origin Carib Israeli NE NE MIRAGE MIRAGE Mayo Mayo Mayo All Hisp Arab FAD spAD Caucasian African Jack Roch Aut Cauc FAD ** ** American # AD 605 111 321 178 279 244 549 433 423 1583 samples Haplo p- 0.005 0.0085 0.005 0.045/ - 0.0025 <0.003 - 0.003 <0.02 value 0.005 C C C 8 G G G 9 10 10 C C C C C C 12 T C C C C 22 T T A T T T T T 23 24 24 T T T TT T C C T T T T T T T T 25 C T C C Rogaeva et al, Nature Genetics 39 :168-177, 2007
1 250 500 750 1000 1250 1500 1750 2000 2214 Amino Acid #s VPS10 Domains YWT D EG F L DL a F N3 T M SNPS 20 20 1 15 rs3824966 24 rs4935774 8 r rs2276346 rs2282649 19 21 26 2 11 rs668387 14 16 25 7 2070045 -18 Ex26 rs1784933 rs578506 rs4935775 rs11600231 T833T rs1010159 9 22 27 rs12364988 3 3 12 12 17 17 rs689021 rs1699102 rs1614735 5 rs582446 rs12285364 rs556349 29 23 rs11218304 10 13 18 rs1131497 rs3824968 4 6 rs641120 28 rs2298813 rs11218340 rs661057 rs560573 rs1133174 3’ 5’ Identical alleles are Identical alleles associated with associated with AD in AD in European Caucasians; Israeli Arabs, Hispanics and Israeli Arabs, Hispanics and Different haplotype associated Different haplotype associated some European Caucasians with AD in African Americans L O C283155 L O C399959 SO RL 1 (177.43 Kb) 120.68 120.84 121.00 121.16 121.32 121.48 Rogaeva et al, Nature Genetics 39 :168-177, 2007 LOC390256 SC5DL
SORL1 is reduced specifically in cortical neurons in late onset AD Control AD AD neocortex neocortical neocortical dendate (bar =100 μ m) pyramidal astrocyte granule neuron (bar =10 μ m) neuron ( μ ) (bar =10 μ m) (bar =10 μ m) Sc cherzer, C. R. et al. Arch Neurol 61, 1200-1205, 2004.
How are sequence variants in SORL1 functionally asso f i ll ociated with AD? i d i h A ? • Do not affect coding sequence or splicing g q p g g; g; • Intronic variants may affect tissue-specifi ic regulation of transcription p < 0.05 NA 20,000 , RL1 mRN • CTT 22-24 haplotype associated with reduce ed transcription in lymphoblasts ( not very robust ); ); SOR 10,000 • Genotype accounts for 14% of variance in n expression level; • Corollary: modifiers of SORL1 expression could be other causes of AD o or Non- Risk Allele p potential therapies. p carrier carrier carrier carrier (n=8) (n=8) Rogaeva et al, Nature Genetics 39 :168-177, 2007
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