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PLoS One. 2010 Sep 20;5(9). pii: e12845. doi: 10.1371/journal.pone.0012845.

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

Author information

  • 1Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA.

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.

PMID:
20862226
[PubMed - indexed for MEDLINE]
PMCID:
PMC2942840
Free PMC Article

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