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SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation

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A Correction to this article was published on 02 November 2022

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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.

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Acknowledgments

We thank Dr. Robert Vassar for providing the BACE1 antibody and Dr. Wanjin Hong for providing the SNX15 plasmid. This study was supported by grants from the National Institutes of Health (R01AG021173, R01AG038710, R01AG044420, R01NS046673, and R21AG049247) and from the National Natural Science Foundation of China (Nos. 81225008, 81161120496, 91332112, 91332114, and U1405222) and Fundamental Research Funds for the Central Universities of China.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Xiamen University, Xiamen, 361102, China

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

  2. Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA

    Huaxi Xu & Yun-wu Zhang

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  1. Tuancheng Feng
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Feng, T., Niu, M., Ji, C. et al. SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation. Mol Neurobiol 53, 3690–3701 (2016). https://doi.org/10.1007/s12035-015-9306-z

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