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- Title
Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease.
- Authors
Tao Ma; Hoeffer, Charles A.; Capetillo-Zarate, Estibaliz; Fangmin Yu; Helen Wong; Lin, Michael T.; Tampellini, Davide; Klann, Eric; Blitzer, Robert D.; Gouras, Gunnar K.
- Abstract
Background: 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 β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD). Methodology/Principal Findings: 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 Aβ1-42. 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 Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD.
- Publication
PLoS ONE, 2010, Vol 5, Issue 9, p1
- ISSN
1932-6203
- Publication type
Academic Journal
- DOI
10.1371/journal.pone.0012845