title: An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
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.
authors: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors: Franco
authors: F
authors: Lombino
authors: Fabrizio
authors: F
authors: Biundo
authors: Robert
authors: R
authors: Tamayev
authors: Ottavio
authors: O
authors: Arancio
authors: Luciano
authors: L
authors: D'Adamio
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D008569:Memory Disorders / Q000503:physiopathology*; D008570:Memory, Short-Term; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D013912:Threonine / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D013912:Threonine