Sorting nexin 27 regulates A? production through modulating ?-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 ?-amyloid (A?) generation by modulating ?-secretase activity. Downregulation of SNX27 using RNAi increased A? production, whereas overexpression of full-length SNX27, but not SNX27?PDZ, reversed the RNAi-mediated A? elevation. Moreover, genetic deletion of Snx27 promoted A? production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal A? levels in a transgenic AD mouse model. SNX27 associates with the ?-secretase complex subunit presenilin 1; this interaction dissociates the ?-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for A?-dependent pathogenesis in both DS and AD.

SUBMITTER: Wang X 

PROVIDER: S-EPMC4328673 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature