Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease.

ABSTRACT: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and ?-amyloid (A?)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD).We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous A?1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented A?-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal A?42 with mTOR.These data support the notion that the mTOR pathway modulates A?-related synaptic dysfunction in AD.

SUBMITTER: Ma T 

PROVIDER: S-EPMC2942840 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature