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

Xin Wang, Timothy Huang, Yingjun Zhao, Qiuyang Zheng, Robert C. Thompson, Guojun Bu, Yun wu Zhang, Wanjin Hong, Huaxi Xu

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1023-1033
Number of pages11
JournalCell reports
Volume9
Issue number3
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wang, X., Huang, T., Zhao, Y., Zheng, Q., Thompson, R. C., Bu, G., Zhang, Y. W., Hong, W., & Xu, H. (2014). Sorting nexin 27 regulates Aβ production through modulating γ-secretase activity. Cell reports, 9(3), 1023-1033. https://doi.org/10.1016/j.celrep.2014.09.037