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