Title |
An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss
|
---|---|
Published in |
PLOS ONE, February 2013
|
DOI | 10.1371/journal.pone.0057120 |
Pubmed ID | |
Authors |
Franco Lombino, Fabrizio Biundo, Robert Tamayev, Ottavio Arancio, Luciano D’Adamio |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 8% |
Spain | 1 | 4% |
Unknown | 21 | 88% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 7 | 29% |
Researcher | 6 | 25% |
Student > Master | 4 | 17% |
Professor | 2 | 8% |
Student > Bachelor | 1 | 4% |
Other | 0 | 0% |
Unknown | 4 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 8 | 33% |
Neuroscience | 5 | 21% |
Biochemistry, Genetics and Molecular Biology | 2 | 8% |
Medicine and Dentistry | 2 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 4% |
Other | 1 | 4% |
Unknown | 5 | 21% |