期刊
JOURNAL OF CELL BIOLOGY
卷 183, 期 2, 页码 339-352出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200804075
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资金
- Ministry of Health, Labor, and Welfare
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Fugaku Trust for Medicinal Research
- Suzuken Memorial Foundation
Neuronal activity has an impact on beta cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-beta peptide (A beta). However, the molecular mechanisms underlying this effect remain to be elucidated. Cholesterol dependency of beta cleavage prompted us to analyze immunoisolated APP-containing detergent-resistant membranes from rodent brains. We found syntaxin 1 as a key molecule for activity-dependent regulation of APP processing in cholesterol-dependent microdomains. In living cells, APP associates with syntaxin 1-containing microdomains through X11-Munc18, which inhibits the APP-BACE1 interaction and beta cleavage via microdomain segregation. Phosphorylation of Munc18 by cdk5 causes a shift of APP to BACE1-containing microdomains. Neuronal hyperactivity, implicated in A beta overproduction, promotes the switching of APP microdomain association as well as beta cleavage in a partially cdk5-dependent manner. We propose that microdomain switching is a mechanism of cholesterol- and activity-dependent regulation of APP processing in neurons.
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