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Title
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Genetic association of **CR1** with Alzheimer's disease : a tentative disease mechanism
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Neurobiology of aging. - Fayetteville, N.Y.
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Publication
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Fayetteville, N.Y.
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2012
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ISSN
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0197-4580
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DOI
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10.1016/J.NEUROBIOLAGING.2012.07.001
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Volume/pages
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33
:12
(2012)
, 8 p.
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Article Reference
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2949
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ISI
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000310200000027
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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