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

Overview

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 date

  • January 1, 2010

Full Author List

  • Ma T; Hoeffer CA; Capetillo-Zarate E; Yu F; Wong H; Lin MT; Tampellini D; Klann E; Blitzer RD; Gouras GK

Other Profiles

Additional Document Info

volume

  • 5

issue

  • 9