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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: Publikationen MPI-CBG 2008     Display Documents



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ID: 414413.0, MPI für molekulare Zellbiologie und Genetik / Publikationen MPI-CBG 2008
Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons
Authors:Schneider, Anja; Rajendran, Lawrence; Honsho, Masanori; Gralle, Matthias; Donnert, Gerald; Wouters, Fred; Hell, Stefan W; Simons, Mikael
Date of Publication (YYYY-MM-DD):2008
Title of Journal:Journal of Neuroscience
Volume:28
Issue / Number:11
Start Page:2874
End Page:2882
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:The flotillins/reggie proteins are associated with noncaveolar membrane microdomains and have been implicated in the regulation of a clathrin- and caveolin-independent endocytosis pathway. Endocytosis is required for the amyloidogenic processing of the amyloid precursor protein (APP) and thus to initiate the release of the neurotoxic beta-amyloid peptide (Abeta), the major component of extracellular plaques found in the brains of Alzheimer's disease patients. Here, we report that small interference RNA-mediated downregulation of flotillin-2 impairs the endocytosis of APP, in both neuroblastoma cells and primary cultures of hippocampal neurons, and reduces the production of Abeta. Similar to tetanus neurotoxin endocytosis, but unlike the internalization of transferrin, clathrin-dependent endocytosis of APP requires cholesterol and adaptor protein-2 but is independent of epsin1 function. Moreover, on a nanoscale resolution using stimulated emission depletion microscopy and by Forster resonance energy transfer with fluorescence lifetime imaging microscopy, we provide evidence that flotillin-2 promotes the clustering of APP at the cell surface. We show that the interaction of flotillin-2 with APP is dependent on cholesterol and that clustering of APP enhances its endocytosis rate. Together, our data suggest that cholesterol/flotillin-dependent clustering of APP may stimulate the internalization into a specialized clathrin-dependent endocytosis pathway to promote amyloidogenic processing.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:n.n.
Affiliations:MPI f�r molekulare Zellbiologie und Genetik
Identifiers:LOCALID:1168
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