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

Abstract

Background: β-site APP cleaving enzyme 1 (BACE1) cleaves β-amyloid precursor protein (APP) to initiate the production of β-amyloid (Aβ), the prime culprit in Alzheimer’s disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect Aβ generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/Aβ 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 γ-secretase components, but dramatically reduces the levels of Aβ, soluble APPβ and APP β-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect γ-secretase activity or in vitro β-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 β-processing of APP for Aβ 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 β-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.