Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism
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- 作者：Lili-Naz Hazrati ; Caroline Van Cauwenberghe ; Patricia L. Brooks ; Nathalie Brouwers ; Mahdi Ghani ; Christine Sato ; Marc Cruts ; Kristel Sleegers ; Peter St. George-Hyslop ; Christine Van Broeckhoven ; Ekaterina Rogaeva
- 关键词：Genetic risk ; Alzheimer's disease ; Copy number variation ; CR1 ; Isoform
- 刊名：Neurobiology of Aging
- 出版年：2012
- 出版时间：December, 2012
- 年：2012
- 卷：33
- 期：12
- 页码：2949.e5-2949.e12
- 全文大小：1384 K
文摘
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.