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

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 de...

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Bibliographic Details
Published in:The Journal of cell biology 2008-10, Vol.183 (2), p.339-352
Main Authors: Sakurai, Takashi, Kaneko, Kumi, Okuno, Misako, Wada, Koji, Kashiyama, Taku, Shimizu, Hideaki, Akagi, Takumi, Hashikawa, Tsutomu, Nukina, Nobuyuki
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases - metabolism
Amyloids
Animals
Antibodies
Aspartic Acid Endopeptidases - metabolism
Biochemistry
Casks
Cholesterol
Cholesterol - deficiency
Cholesterols
Cyclin-Dependent Kinase 5 - metabolism
Detergents - pharmacology
Humans
Lipids
Membrane Microdomains - drug effects
Membrane Microdomains - metabolism
Membrane Microdomains - ultrastructure
Membranes
Mice
Munc18 Proteins - metabolism
Nerve Tissue Proteins - metabolism
Neurons
Neurons - drug effects
Neurons - enzymology
Peptides
Physiological regulation
Polyethylene Glycols - pharmacology
Prions - metabolism
Protein precursors
Protein Processing, Post-Translational - drug effects
Proteins
Rafts
Rats
Subcellular Fractions - drug effects
Subcellular Fractions - metabolism
Syntaxin 1 - metabolism
Thy-1 Antigens - metabolism
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200804075