Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases alpha- and ß-secretase is a key regulatory event in the generation of the Alzheimer’s disease amyloid ß peptide (Aß). ß-secretase catalyzes the first step in Aß-generation, whereas a-secretase cleaves within the Aß domain, prevents Aß generation and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP alpha-secretase cleavage and Aß 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 alpha-secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phospho-protein. Exogenous expression of SNX33 in cultured cells increased APP alpha-secretase cleavage four-fold, but surprisingly had little effect on ß-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 a-secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP a-secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP alpha-secretase cleavage.