Abstract
BackgroundThe 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 FindingsWe 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/SignificanceThese data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD.
Highlights
Increasing evidence supports the idea that in Alzheimer’s disease (AD) functional impairment of synaptic plasticity develops before neurodegeneration
We report that mammalian target of rapamycin (mTOR) signaling is inhibited both in cultured neurons and hippocampal slices from AD transgenic mice and in wild-type (WT) hippocampal slices exposed to exogenous Ab1-42, and that this mTOR dysregulation correlated with impairment in synaptic plasticity
Compared to wild-type (WT) littermate slices, hippocampal slices from Tg2576 mice showed a significant decrease in the levels of p70 S6 kinase (p70S6K) phosphorylated at threonine 389, a site phosphorylated by mTOR and used as a readout for mTOR activity [18] (Figure 1A)
Summary
Increasing evidence supports the idea that in Alzheimer’s disease (AD) functional impairment of synaptic plasticity develops before neurodegeneration. Formation of Ab-derived plaques, a pathological hallmark of AD, develops after accumulation of soluble Ab oligomers. These findings have focused attention on the early, pre-plaque stage of AD when synaptic plasticity is already impaired by Ab [3,4]. One of the central questions is how abnormal Ab accumulation in the brain causes synaptic dysfunction and cognitive deficits. We explored the relationship between the mTOR pathway and b-amyloid (Ab)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer’s disease (AD)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
