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The processing of amyloid precursor protein (APP) is a key event in the pathogenesis of Alzheimer disease.Certain cleavage pathways tend to occur in particular subcellular compartments when APP travels intracellularly.As a result, the processing of APP is greatly influenced by factors which regulate its trafficking.Here we report that SCG 10, a membrane-associated protein, directly interacts with the KFFEQ motif of APP intracellular domain (AICD) and promotes the non-amyloidogenic processing of APP.Knockdown of SCG 10 leads to a reduction of α-cleaved products, sAPPα and αCTF, and an increase of two Aβ species, Aβ1-40 and Aβ1-42.Furthermore, elevated level of SCG10 results in the accumulation of APP in the post-Golgi vesicles and cell surface by facilitating anterograde trafficking of APP out of the Golgi apparatus.In addition, the ability of SCG10 to regulate APP processing is significantly compromised when the palmitoylation-mediated membrane-anchoring of SCG 10 is disrupted.Taken together, these results suggest that SCG10, as a binding partner of APP, paly a critical role in the regulation of APP processing and may play a potential role in the prevention of Alzheimer disease.