| First Author | Sakurai T | Year | 2008 |
| Journal | J Cell Biol | Volume | 183 |
| Issue | 2 | Pages | 339-52 |
| PubMed ID | 18936252 | Mgi Jnum | J:140648 |
| Mgi Id | MGI:3814263 | Doi | 10.1083/jcb.200804075 |
| Citation | Sakurai T, et al. (2008) Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing. J Cell Biol 183(2):339-52 |
| abstractText | Neuronal activity has an impact on beta cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-beta peptide (Abeta). 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 Abeta 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. |
