Abstract
BackgroundAmyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer’s disease (AD). Aβ 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.MethodsIn 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.ResultsWe 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 Aβ. 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 Aβ.ConclusionsWe show that SNX4 regulates BACE1 trafficking. Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1-mediated β-processing of APP and subsequent Aβ generation.
Highlights
Amyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer’s disease (AD)
Altered levels of sorting nexin-4 (SNX4) in the brains of patients with AD and APP/PS1 mice To investigate whether SNX4 is involved in the pathogenesis of AD, we compared the levels of SNX4 protein between controls and patients with AD
SNX4 levels in the brains of 6-month-old APP/PS1 mice were increased compared with wild-type mice, whereas SNX4 levels were decreased in the brains of 24-month-old APP/PS1 mice compared with controls (Fig. 1, Additional file 1: Figure S1)
Summary
Amyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer’s disease (AD). The Aβ40–42 peptide is derived from the amyloid precursor protein (APP) via the action of two membrane-bound proteolytic enzymes: β- and γ-secretase. Β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that mediates the β-secretase cleavage, yielding a soluble ectodomain-secreted APP derivative (sAPPβ), as well as to a membrane-anchored C-terminal fragment (CTF) that subsequently undergoes presenilin-. The trimer of VPS26-VPS29-VSP35 provides cargo selectivity through direct binding of VPS35 to the cytosolic tail of several cargo proteins (e.g., cation-independent mannose-6phosphate receptor) [15] The assembly of these two subcomplexes allows the SNX-BAR retromer to coordinate the formation/stabilization of endosomal tubules selectively enriched with the appropriate cargo for endosome-to-TGN retrieval [16, 17]
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