Sorting Nexin 27 Regulates Aβ Production through Modulating γ-Secretase Activity
Copyright policy )Sorting Nexin 27 Regulates Aβ Production through Modulating γ-Secretase Activity
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.
- Hong Kong University of Science and Technology (香港科技大學) China (People's Republic of)
- Neurosciences Institute United States
- Hong Kong Polytechnic University China (People's Republic of)
- Center for Neurosciences United States
- Sanford Burnham Prebys Medical Discovery Institute United States
Neurons, Amyloid beta-Peptides, Receptors, Notch, QH301-705.5, Mice, Transgenic, Models, Biological, Disease Models, Animal, Protein Subunits, HEK293 Cells, Alzheimer Disease, Presenilin-1, Animals, Humans, Biology (General), Amyloid Precursor Protein Secretases, Sorting Nexins, Gene Deletion, HeLa Cells, Protein Binding
Neurons, Amyloid beta-Peptides, Receptors, Notch, QH301-705.5, Mice, Transgenic, Models, Biological, Disease Models, Animal, Protein Subunits, HEK293 Cells, Alzheimer Disease, Presenilin-1, Animals, Humans, Biology (General), Amyloid Precursor Protein Secretases, Sorting Nexins, Gene Deletion, HeLa Cells, Protein Binding
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