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The Journal of Neuroscience, March 12, 2008, 28(11):2874-2882; doi:10.1523/JNEUROSCI.5345-07.2008

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Neurobiology of Disease
Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons

Anja Schneider,^1,2,5 * Lawrence Rajendran,^6 * Masanori Honsho,⁶ Matthias Gralle,⁴ Gerald Donnert,⁷ Fred Wouters,⁴ Stefan W. Hell,⁷ and Mikael Simons^1,3,5

¹Centre for Biochemistry and Molecular Cell Biology, ²Department of Psychiatry and Psychotherapy, ³Department of Neurology, and ⁴Laboratory for Molecular and Cellular Systems, Department of Neuro- and SensoryPhysiology, University of Göttingen, 37073 Göttingen, Germany, ⁵Max-Planck-Institute for Experimental Medicine, 37075 Goettingen, Germany, ⁶Max-Planck-Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany, and ⁷Max-Planck-Institute of Biophysical Chemistry, 37077 Göttingen, Germany

Correspondence should be addressed to Dr. Mikael Simons, Centre for Biochemistry and Molecular Cell Biology, University of Göttingen, Humboldallee 23, 37073 Göttingen, Germany. Email: msimons{at}gwdg.de

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 β-amyloid peptide (Aβ), 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 Aβ. 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 Förster 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.

Key words: neurons; endocytosis; amyloid β; Alzheimer's disease; flotillin; cholesterol

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Received Aug. 24, 2007; accepted Dec. 24, 2007.

Correspondence should be addressed to Dr. Mikael Simons, Centre for Biochemistry and Molecular Cell Biology, University of Göttingen, Humboldallee 23, 37073 Göttingen, Germany. Email: msimons{at}gwdg.de

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