2013 Articles
An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss
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^668Ala mutation (APPTA 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.
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Also Published In
- Title
- PLoS ONE
- DOI
- https://doi.org/10.1371/journal.pone.0057120
More About This Work
- Academic Units
- Pathology and Cell Biology
- Published Here
- July 10, 2013