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Published online October 20, 2008
doi:10.1083/jcb.200804075
The Journal of Cell Biology, Vol. 183, No. 2, 339-352
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Sakurai et al.
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Article

Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing



Takashi Sakurai1,2,4, Kumi Kaneko1,2, Misako Okuno1,2, Koji Wada1, Taku Kashiyama1,4, Hideaki Shimizu1, Takumi Akagi3, Tsutomu Hashikawa3, and Nobuyuki Nukina1,2

1 Laboratory for Structural Neuropathology, 2 Laboratory for Neurodegeneration Signal, and 3 Laboratory for Neural Architecture, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
4 Department of Pharmacology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan

Correspondence to N. Nukina: nukina{at}brain.riken.jp

Neuronal activity has an impact on β cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-β peptide (Aβ). However, the molecular mechanisms underlying this effect remain to be elucidated. Cholesterol dependency of β 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 β cleavage via microdomain segregation. Phosphorylation of Munc18 by cdk5 causes a shift of APP to BACE1-containing microdomains. Neuronal hyperactivity, implicated in Aβ overproduction, promotes the switching of APP microdomain association as well as β 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.

Abbreviations used in this paper: Aβ, amyloid-β peptide; AD, Alzheimer's disease; APLP, amyloid precursor-like protein; APP, amyloid precursor protein; CASK, calcium/calmodulin-dependent serine protein kinase; CID, CASK-interacting domain; CTF, C-terminal fragment; DIV, days in vitro; DRM, detergent-resistant membrane; FL, full length; GPI, glycosyl-phosphatidylinositol; IP, immunoprecipitation; MβCD, methyl-β-cyclodextrin; MBS, MES-buffered saline; MID, Munc18 interaction domain; MS, mass spectrometry; OG, octylglucoside; PrP, prion protein; PTX, picrotoxin; sAPP, secreted APP; VSVG, vesicular stomatitis virus glycoprotein; WB, Western blot.

© 2008 Sakurai et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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