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

T Ma, CA Hoeffer, E Capetillo-Zarate, F Yu, H Wong… - PloS one, 2010 - journals.plos.org
T Ma, CA Hoeffer, E Capetillo-Zarate, F Yu, H Wong, MT Lin, D Tampellini, E Klann
PloS one, 2010journals.plos.org
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 …
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.
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