@article{f453dd4273834478a4cd9fcbb7f10ff0,
title = "Sorting nexin 27 regulates Aβ production through modulating γ-secretase activity",
abstract = "Patients with Down syndrome (DS) invariably develop Alzheimer's disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating β-amyloid (Aβ) generation by modulating γ-secretase activity. Downregulation of SNX27 using RNAi increased Aβ production, whereas overexpression of full-length SNX27, but not SNX27ΔPDZ, reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.",
author = "Xin Wang and Timothy Huang and Yingjun Zhao and Qiuyang Zheng and Thompson, {Robert C.} and Guojun Bu and Zhang, {Yun wu} and Wanjin Hong and Huaxi Xu",
note = "Funding Information: We thank T. Golde and C. Ceballos (University of Florida) for generating AAV; J-Y. Hur and Y-M. Li (Memorial Sloan-Kettering Cancer Center) for technical assistance; B. Ranscht, W.C. Mobley, E.H. Koo, S.A. Lipton, and G. Thinakaran for helpful discussion; A. Brzozowska-Prechtl and L. Lacarra for technical help; and P. Slesinger (Mount Sinai School of Medicine) and R. Vassar (Northwestern University) for sharing reagents. This work was supported in part by US NIH grants (R01 AG038710, R01 AG021173, R01 NS046673, R01 AG030197, and R01 AG044420 to H.X.) and grants from the Alzheimer{\textquoteright}s Association (to H.X. and Y.-w.Z.) and the Global Down Syndrome Foundation (DSADIIP-13-283543, to H.X.), the American Health Assistance Foundation (to H.X.), National Natural Science Foundation of China (81202419, 81225008, 81161120496, 91332112, and 91332114), the 973 Prophase Project (2010CB535004 to Y.-w.Z.), and Natural Science Funds for Distinguished Young Scholar of Fujian Province (2009J06022 to Y.-w.Z.). Y.-w.Z. is supported by the Program for New Century Excellent Talents in Universities (NCET), the Fundamental Research Funds for the Central Universities, and the Fok Ying Tung Education Foundation. Publisher Copyright: {\textcopyright} 2014 The Authors.",
year = "2014",
doi = "10.1016/j.celrep.2014.09.037",
language = "English (US)",
volume = "9",
pages = "1023--1033",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}