| First Author | Lombino F | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 2 | Pages | e57120 |
| PubMed ID | 23451158 | Mgi Jnum | J:198292 |
| Mgi Id | MGI:5496309 | Doi | 10.1371/journal.pone.0057120 |
| Citation | Lombino F, et al. (2013) An intracellular threonine of amyloid-beta precursor protein mediates synaptic plasticity deficits and memory loss. PLoS One 8(2):e57120 |
| abstractText | 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. |
