Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons
2008 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons
Schneider, A. ; Rajendran, L.; Honsho, M.; Gralle, M. ; Donnert, G.; Wouters, F. S. & Hell, S. et al. (2008)
The Journal of Neuroscience, 28(11) pp. 2874-2882. DOI: https://doi.org/10.1523/JNEUROSCI.5345-07.2008
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- Authors
- Schneider, Anja ; Rajendran, Lawrence; Honsho, Masanori; Gralle, Matthias ; Donnert, Gerald; Wouters, Fred S. ; Hell, Stefan ; Simons, Mikael
- Abstract
- 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 (A beta), 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 A beta. 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.
- Issue Date
- 2008
- Journal
- The Journal of Neuroscience
- ISSN
- 0270-6474
- Language
- English