Sorting nexin 27 regulates Aβ production through modulating γ-secretase activity

Cell Rep. 2014 Nov 6;9(3):1023-33. doi: 10.1016/j.celrep.2014.09.037. Epub 2014 Oct 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / biosynthesis*
  • Animals
  • Disease Models, Animal
  • Gene Deletion
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice, Transgenic
  • Models, Biological
  • Neurons / metabolism
  • Neurons / pathology
  • Presenilin-1 / metabolism
  • Protein Binding
  • Protein Subunits / metabolism
  • Receptors, Notch / metabolism
  • Sorting Nexins / metabolism*


  • Amyloid beta-Peptides
  • Presenilin-1
  • Protein Subunits
  • Receptors, Notch
  • SNX27 protein, human
  • Snx27 protein, mouse
  • Sorting Nexins
  • Amyloid Precursor Protein Secretases