SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation

Tuancheng Feng, Mengmeng Niu, Chengxiang Ji, Yuehong Gao, Jing Wen, Guojun D Bu, Huaxi Xu, Yun wu Zhang

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Amyloid-β (Aβ) peptide plays an essential role in the pathogenesis of Alzheimer’s disease (AD) and is generated from amyloid-β precursor protein (APP) through sequential proteolytic cleavages by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Trafficking dysregulation of APP, BACE1, and γ-secretase may affect Aβ generation and disease pathogenesis. Sorting nexin 15 (SNX15) is known to regulate protein trafficking. Here, we report that SNX15 is abundantly expressed in mouse neurons and astrocytes. In addition, we show that although not affecting the protein levels of APP, BACE1, and γ-secretase components and the activity of BACE1 and γ-secretase, overexpression and downregulation of SNX15 reduce and promote Aβ production, respectively. Furthermore, we find that overexpression of SNX15 increases APP protein levels in cell surface through accelerating APP recycling, whereas downregulation of SNX15 has an opposite effect. Finally, we show that exogenous expression of human SNX15 in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Aβ pathology in the hippocampus and improve short-term working memory in the APPswe/PSEN1dE9 double transgenic AD model mice. Together, our results suggest that SNX15 regulates the recycling of APP to cell surface and, thus, its processing for Aβ generation.

Original languageEnglish (US)
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Jun 27 2015
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • Amyloid-β precursor protein
  • SNX15
  • Trafficking

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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  • Cite this

    Feng, T., Niu, M., Ji, C., Gao, Y., Wen, J., Bu, G. D., Xu, H., & Zhang, Y. W. (Accepted/In press). SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation. Molecular Neurobiology. https://doi.org/10.1007/s12035-015-9306-z