An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss

Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2013; 8(2):e57120. DOI: 10.1371/journal.pone.0057120
Source: PubMed

ABSTRACT Mutations in ß and 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 FDD, 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 of ß-CTF because phosphorylation of Thr is increased in AD cases. We created a knock-in mouse bearing a ThrAla mutation ( mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDD 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 is a viable therapeutic strategy for human dementias.

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    • "APP is involved in synapse formation, dendritic spine formation, synaptic transmission, neurites outgrowth, learning and memory, motility and development [13]. Though all APP metabolites have biological functions [14]–[20], phenomenological observations underline the key physiological and pathological role of the APP intracellular domain [21]–[26]. Mutation of single APP intracellular residues can have dramatically opposite effects. For example, mice carrying the Y682G (using the APP-695 isoform numbering) mutation in the intracellular domain, present functional deficits similar to that of APP KO mice, including cognitive and neuromuscular junctions deficits [23], [25]. "
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