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Sorting nexin-4 regulates β-amyloid production by modulating β-site-activating cleavage enzyme-1.
- Source :
-
Alzheimer's research & therapy [Alzheimers Res Ther] 2017 Jan 21; Vol. 9 (1), pp. 4. Date of Electronic Publication: 2017 Jan 21. - Publication Year :
- 2017
-
Abstract
- Background: 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). 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.<br />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.<br />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 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.<br />Conclusions: We 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.
- Subjects :
- Aged
Aged, 80 and over
Amyloid beta-Protein Precursor genetics
Amyloid beta-Protein Precursor metabolism
Animals
Brain metabolism
Brain pathology
Cell Membrane metabolism
Cell Membrane pathology
HEK293 Cells
HeLa Cells
Humans
Male
Mice, Transgenic
Neurons metabolism
Neurons pathology
Presenilin-1 genetics
Presenilin-1 metabolism
Amyloid Precursor Protein Secretases metabolism
Aspartic Acid Endopeptidases metabolism
Sorting Nexins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1758-9193
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Alzheimer's research & therapy
- Publication Type :
- Academic Journal
- Accession number :
- 28109317
- Full Text :
- https://doi.org/10.1186/s13195-016-0232-8