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

Tao Ma, Charles A. Hoeffer, Estibaliz Capetillo-Zarate, Fangmin Yu, Helen Wong, Michael T. Lin, Davide Tampellini, Eric Klann, Robert D. Blitzer, Gunnar K. Gouras

Research output: Contribution to journalArticle

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 (Ab)-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 Ab42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Ab-related synaptic dysfunction in AD.

Original languageEnglish (US)
Article numbere12845
Pages (from-to)1-10
Number of pages10
JournalPLoS One
Volume5
Issue number9
DOIs
StatePublished - 2010

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Neuronal Plasticity
Sirolimus
Alzheimer disease
Plasticity
Alzheimer Disease
animal models
disease models
Long-Term Potentiation
amyloid
protein kinases
Tacrolimus Binding Proteins
Glycogen Synthase Kinase 3
Biological Phenomena
binding proteins
pathogenesis
Confocal microscopy
Genetic Models
Amyloid
Confocal Microscopy
Protein Kinases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ma, T., Hoeffer, C. A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M. T., ... Gouras, G. K. (2010). Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS One, 5(9), 1-10. [e12845]. https://doi.org/10.1371/journal.pone.0012845

Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. / Ma, Tao; Hoeffer, Charles A.; Capetillo-Zarate, Estibaliz; Yu, Fangmin; Wong, Helen; Lin, Michael T.; Tampellini, Davide; Klann, Eric; Blitzer, Robert D.; Gouras, Gunnar K.

In: PLoS One, Vol. 5, No. 9, e12845, 2010, p. 1-10.

Research output: Contribution to journalArticle

Ma, T, Hoeffer, CA, Capetillo-Zarate, E, Yu, F, Wong, H, Lin, MT, Tampellini, D, Klann, E, Blitzer, RD & Gouras, GK 2010, 'Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease', PLoS One, vol. 5, no. 9, e12845, pp. 1-10. https://doi.org/10.1371/journal.pone.0012845
Ma, Tao ; Hoeffer, Charles A. ; Capetillo-Zarate, Estibaliz ; Yu, Fangmin ; Wong, Helen ; Lin, Michael T. ; Tampellini, Davide ; Klann, Eric ; Blitzer, Robert D. ; Gouras, Gunnar K. / Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. In: PLoS One. 2010 ; Vol. 5, No. 9. pp. 1-10.
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