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Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases α- and β-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid β peptide (Aβ). β-Secretase catalyzes the first step in Aβ generation, whereas α-secretase cleaves within the Aβ domain, prevents Aβ generation, and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP α-secretase cleavage and Aβ generation. To explore the contributory pathways, we carried out an expression cloning screen. We identified a novel member of the sorting nexin (SNX) family of endosomal trafficking proteins, called SNX33, as a new activator of APP α-secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phosphoprotein. Exogenous expression of SNX33 in cultured cells increased APP α-secretase cleavage 4-fold but surprisingly had little effect on β-secretase cleavage. This effect was similar to the expression of the dominant negative dynamin-1 mutant K44A. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner. This led to an increase of APP at the plasma membrane, where α-secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP α-secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP α-secretase cleavage. [ABSTRACT FROM AUTHOR]