Sorting Nexin 27 Regulates Aβ Production through Modulating γ-Secretase Activity

•SNX27 regulates γ-secretase cleavage of APP and consequent Aβ generation•SNX27 binds to presenilin 1 and regulates γ-secretase complex formation and activity•Transduction of SNX27 reduces Aβ in an AD mouse model•Snx27 deletion promotes Aβ generation and neuronal loss in an AD mouse model

SummaryPatients 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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