A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death

Nat Med. 2014 Dec;20(12):1452-7. doi: 10.1038/nm.3736. Epub 2014 Nov 24.


We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides
  • Animals
  • CA3 Region, Hippocampal / cytology
  • Cell Death / genetics
  • Female
  • Genetic Predisposition to Disease
  • Glutamic Acid
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Netrin Receptors
  • Neurons / metabolism*
  • Rats
  • Receptors, Cell Surface / genetics*
  • Receptors, Nerve Growth Factor / genetics*
  • Staurosporine


  • Amyloid beta-Peptides
  • Netrin Receptors
  • Receptors, Cell Surface
  • Receptors, Nerve Growth Factor
  • UNC5C protein, human
  • UNC5C protein, rat
  • Unc5c protein, mouse
  • Glutamic Acid
  • Staurosporine