Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 30, Pages 7996-8011Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0206-16.2016
Keywords
Alzheimer's disease; APP; endosome recycling; protein trafficking; SNX27; SORLA
Categories
Funding
- National Institutes of Health Grants [R01AG021173, R01AG038710, R01AG044420, R01NS046673, R21AG049247]
- Alzheimer's Association [C4C-15-369446, DSADIIP-13-283543, C4C-15-368951]
- Shiley-Marcos Alzheimer's Disease Research Center University of California San Diego Grant [ADRC 201559226]
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Proteolytic generation of amyloidogenic amyloid beta (A beta) fragments from the amyloid precursor protein (APP) significantly contributes to Alzheimer's disease (AD). Although amyloidogenic APP proteolysis can be affected by trafficking through genetically associated AD components such as SORLA, how SORLA functionally interacts with other trafficking components is yet unclear. Here, we report that SNX27, an endosomal trafficking/recycling factor and a negative regulator of the gamma-secretase complex, binds to the SORLA cytosolic tail to form a ternary complex with APP. SNX27 enhances cell surface SORLA and APP levels in human cell lines and mouse primary neurons, and depletion of SNX27 or SORLA reduces APP endosome-to-cell surface recycling kinetics. SNX27 overexpression enhances the generation of cell surface APP cleavage products such as soluble alpha-APP C-terminal fragment (CTF alpha) in a SORLA-dependent manner. SORLA-mediated A beta reduction is attenuated by downregulation of SNX27. This indicates that an SNX27/SORLA complex functionally interacts to limit APP distribution to amyloidogenic compartments, forming a non-amyloidogenic shunt to promote APP recycling to the cell surface.
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