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Sorting nexin 27 regulates Aβ production through modulating γ-secretase activity.

Authors
  • Wang, Xin
  • Huang, Timothy
  • Zhao, Yingjun
  • Zheng, Qiuyang
  • Thompson, Robert C
  • Bu, Guojun
  • Zhang, Yun-wu
  • Hong, Wanjin
  • Xu, Huaxi
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Nov 06, 2014
Volume
9
Issue
3
Pages
1023–1033
Identifiers
DOI: 10.1016/j.celrep.2014.09.037
PMID: 25437557
Source
Medline
License
Unknown

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.

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