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Cell Rep. 2014 Nov 6;9(3):1023-33. doi: 10.1016/j.celrep.2014.09.037. Epub 2014 Oct 23.

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

Author information

1
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361005, China; Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
2
Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
3
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361005, China.
4
Institute for Biomedical Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China; Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
5
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361005, China; Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: xuh@sanfordburnham.org.

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.

PMID:
25437557
PMCID:
PMC4328673
DOI:
10.1016/j.celrep.2014.09.037
[Indexed for MEDLINE]
Free PMC Article

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