An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss

PLoS One. 2013;8(2):e57120. doi: 10.1371/journal.pone.0057120. Epub 2013 Feb 22.

Abstract

Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr(668) of ß-CTF because phosphorylation of Thr(668) is increased in AD cases. We created a knock-in mouse bearing a Thr(668)Ala mutation (APP(TA) mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr(668) is a viable therapeutic strategy for human dementias.

Publication types

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

MeSH terms

  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / physiology
  • Animals
  • Memory Disorders / physiopathology*
  • Memory, Short-Term
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity / physiology*
  • Threonine / physiology*

Substances

  • Amyloid beta-Protein Precursor
  • Threonine