Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism

被引：61

作者：

Hazrati, Lili-Naz ^{[1
,2
]}

Van Cauwenberghe, Caroline ^{[3
,4
]}

Brooks, Patricia L. ^{[1
]}

Brouwers, Nathalie ^{[3
,4
]}

Ghani, Mahdi ^{[1
]}

Sato, Christine ^{[1
]}

Cruts, Marc ^{[3
,4
]}

Sleegers, Kristel ^{[3
,4
]}

St George-Hyslop, Peter ^{[1
,2
,5
,6
]}

Van Broeckhoven, Christine ^{[3
,4
]}

Rogaeva, Ekaterina ^{[1
,2
]}

机构：

[1] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada

[2] Univ Toronto, Dept Med, Toronto, ON, Canada

[3] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

[4] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium

[5] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England

[6] Univ Cambridge, Dept Clin Neurosci, Cambridge, England

来源：

NEUROBIOLOGY OF AGING | 2012年 / 33卷 / 12期

基金：

加拿大健康研究院; 美国国家卫生研究院; 英国惠康基金;

关键词：

Genetic risk; Alzheimer's disease; Copy number variation; CR1; Isoform; GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; COMMON VARIANTS; CLU; CD2AP; EPHA1; CD33;

D O I：

10.1016/j.neurobiolaging.2012.07.001

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

CR1 is a novel Alzheimer's disease (AD) gene identified by genome-wide association studies (GWAS). Recently, we showed that AD risk could be explained by an 18-kilobase insertion responsible for the complement component (3b/4b) receptor 1 (CR1)-S isoform. We investigated the relevance of the CR1 isoforms to AD in a Canadian dataset. Also, we genotyped rs4844610 tagging the GWAS-significant CR1 single nucleotide polymorphisms. Individuals with F/S genotype had a 1.8 times increased risk for AD compared with F/F genotype (p-adjusted = 0.003), while rs4844610 was only marginally significant (p-adjusted = 0.024). The analyses of brain samples demonstrated that the CR1-S isoform is expressed at lower protein levels than CR1-F (p < 0.0001) hence likely associated with increased complement activation. Intriguingly, our neuropathological results show that the pattern of CR1 expression in neurons is different between the F/F and F/S genotypes (filiform vs. vesicular-like profiles). Furthermore, double labeling studies supported a differential distribution of CR1 in neurons (endoplasmic reticulum intermediate compartment vs. lysosomes). These observations indicate that the CR1-S and CR1-F isoforms could be processed in different ways in neurons. In conclusion, our results support that the CR1-S isoform explains the GWAS signals and open a novel prospect for the investigation of CR1-related disease mechanisms. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：2949.e5 / 2949.e12

页数：8

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