Sorting nexin-4 regulates \u3b2-amyloid production by modulating \u3b2-site-activating cleavage enzyme-1

Abstract Background Amyloid precursor protein (APP) is cleaved by \u3b2-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce \u3b2-amyloid (A\u3b2), a critical pathogenic peptide in Alzheimer\u2019s disease (AD). A\u3b2 generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. Although sorting nexin (SNX) family proteins regulate this trafficking, the relevance and role of sorting nexin-4 (SNX4) regarding AD has not been studied yet. Methods In this study, human brain tissue and APP/PS1 mouse brain tissue were used to check the disease relevance of SNX4. To investigate the role of SNX4 in AD pathogenesis, several experiments were done, such as coimmunoprecipitation, Western blotting, immunohistochemistry, and gradient fractionation. Results We found that SNX4 protein levels changed in the brains of patients with AD and of AD model mice. Overexpression of SNX4 significantly increased the levels of BACE1 and A\u3b2. Downregulation of SNX4 had the opposite effect. SNX4 interacts with BACE1 and prevents BACE1 trafficking to the lysosomal degradation system, resulting in an increased half-life of BACE1 and increased production of A\u3b2. Conclusions We show that SNX4 regulates BACE1 trafficking. Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1-mediated \u3b2-processing of APP and subsequent A\u3b2 generation