Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing

Background: beta-site APP cleaving enzyme 1 (BACE1) cleaves beta-amyloid precursor protein (APP) to initiate the production of beta-amyloid (A beta), the prime culprit in Alzheimer's disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect A beta generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/A beta generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation. Results: Herein, we find that SNX12 is widely expressed in brain tissues and is mainly localized in the early endosomes. Overexpression of SNX12 does not affect the steady-state levels of APP, BACE1 or gamma-secretase components, but dramatically reduces the levels of A beta, soluble APP beta and APP beta-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect gamma-secretase activity or in vitro beta-secretase activity. Further studies reveal that SNX12 interacts with BACE1 and downregulation of SNX12 accelerates BACE1 endocytosis and decreases steady-state level of cell surface BACE1. Finally, we find that the SNX12 protein level is dramatically decreased in the brain of AD patients as compared to that of controls. Conclusion: This study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting beta-processing of APP for A beta production. The reduced level of SNX12 in AD brains suggests that an alteration of SNX12 may contribute to AD pathology. Therefore, inhibition of BACE1-mediated beta-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.