2010 Fiscal Year Final Research Report
A novel microdomain-dependent regulatory mechanism of amyloid precursor protein processing
| Project/Area Number |
20300125
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Juntendo University |
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Principal Investigator |
SAKURAI Takashi Juntendo University, 医学部, 教授 (70225845)
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| Co-Investigator(Kenkyū-buntansha) |
NUKINA Nobuyuki (独)理化学研究所, 構造神経病理研究チーム, チームリーダー (10134595)
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| Co-Investigator(Renkei-kenkyūsha) |
KASHIYAMA Taku 順天堂大学, 医学部, 助教 (90338343)
ARAYA Runa 順天堂大学, 医学部, 助教 (10391848)
KAMIKUBO Yuji 順天堂大学, 医学部, 助教 (80509670)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 神経変性疾患 / 痴呆 / 脂質 |
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| Research Abstract |
Beta-cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) in a membrane microdomain is thought to be a critical regulatory event in generating β-amyloid which is central to the pathogenesis of Alzheimer's disease. To investigate the underlying molecular mechanisms of this process, we analyzed immunoisolated, APP-containing, detergent-resistant membranes from mouse brains. APP was associated with cholesterol-dependent microdomains through a network of protein interactions involving X11, Munc18 and syntaxin 1, which largely excluded BACE1. APP-X11-Munc18 interaction mediated inhibitory effects on APP-BACE1 interaction and β-cleavage. We propose a novel regulatory mechanism of APP processing involving microdomain segregation that depends on protein-protein interactions and is controlled by cdk5 phosphorylation.
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