期刊
ANNALS OF NEUROLOGY
卷 69, 期 1, 页码 47-64出版社
WILEY
DOI: 10.1002/ana.22308
关键词
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资金
- National Institutes of Health, National Institute on Aging [R37-AG15473, P01-AG07232, R01-AG09029, R01-AG025259, P30-AG13846]
- Boston University [K23AG034550, R01-AG027944, R01-AG019757]
- Blanchette Hooker Rockefeller Foundation
- Charles S. Robertson Gift from the Banbury Fund
- Merrill Lynch Foundation
- anonymous foundation
- Asklepios-Med (Hungary)
- The Rosalinde and Arthur Gilbert Foundation
- The Taub Institute for Research on Alzheimer's disease and the Aging Brain
- Columbia University
- Alzheimer Society of Canada
- Canadian Institutes of Health Research (CIHR)
- Alzheimer Society of Ontario
- Howard Hughes Medical Institute
- The Wellcome Trust
- Ontario Research Fund
- Alzheimer's Association
- Institut de France
- Paul B. Beeson Career Development Award
- Medical Research Council [MC_G1000734] Funding Source: researchfish
- NATIONAL INSTITUTE ON AGING [R01AG009029, R01AG041797, R01AG037212, R01AG019757, R01AG015473, R37AG015473, U24AG021886, K23AG034550, P30AG013846, R01AG025259, P01AG007232, R01AG027944] Funding Source: NIH RePORTER
- MRC [MC_G1000734] Funding Source: UKRI
Objective: Sorting mechanisms that cause the amyloid precursor protein (APP) and the beta-secretases and gamma-secretases to colocalize in the same compartment play an important role in the regulation of A beta production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of A beta. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. Methods: We analyzed the genetic associations between AD and 16 SORCS1 single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and A beta generation. Results: Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced gamma-secretase activity and A beta levels, the suppression of SorCS1 increased gamma-secretase processing of APP and the levels of A beta. Interpretations: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. ANN NEUROL 2011;69:47-64
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