title: SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation.
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.
authors.affiliation: 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.
authors.forename: Tuancheng
authors.initials: T
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Niu
authors.affiliation: 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.
authors.forename: Chengxiang
authors.initials: C
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: 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.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: 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.|Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: 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. yunzhang@xmu.edu.cn.|Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA. yunzhang@xmu.edu.cn.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
mesh_terms: D000375:Aging / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D006801:Humans; D008570:Memory, Short-Term; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D058305:Sorting Nexins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C429023:SNX15 protein, human; C000625723:Snx15 protein, mouse; D058305:Sorting Nexins; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Amyloid-β; Amyloid-β precursor protein; SNX15; Trafficking