کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6808109 | 1433588 | 2012 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
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چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Aging - Volume 33, Issue 12, December 2012, Pages 2949.e5-2949.e12
Journal: Neurobiology of Aging - Volume 33, Issue 12, December 2012, Pages 2949.e5-2949.e12
نویسندگان
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,