| First Author | Wang X | Year | 2014 |
| Journal | Cell Rep | Volume | 9 |
| Issue | 3 | Pages | 1023-33 |
| PubMed ID | 25437557 | Mgi Jnum | J:271362 |
| Mgi Id | MGI:6274053 | Doi | 10.1016/j.celrep.2014.09.037 |
| Citation | Wang X, et al. (2014) Sorting nexin 27 regulates Abeta production through modulating gamma-secretase activity. Cell Rep 9(3):1023-33 |
| abstractText | 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 beta-amyloid (Abeta) generation by modulating gamma-secretase activity. Downregulation of SNX27 using RNAi increased Abeta production, whereas overexpression of full-length SNX27, but not SNX27DeltaPDZ, reversed the RNAi-mediated Abeta elevation. Moreover, genetic deletion of Snx27 promoted Abeta production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal Abeta levels in a transgenic AD mouse model. SNX27 associates with the gamma-secretase complex subunit presenilin 1; this interaction dissociates the gamma-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Abeta-dependent pathogenesis in both DS and AD. |
