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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 LU ; Klann, Eric ; Blitzer, Robert D. and Gouras, Gunnar K. LU (2010) In PLoS ONE 5(9). p.1-10
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... (More)

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.

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author
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
5
issue
9
article number
e12845
pages
1 - 10
publisher
Public Library of Science
external identifiers
  • pmid:20862226
  • scopus:77958465822
ISSN
1932-6203
DOI
10.1371/journal.pone.0012845
language
English
LU publication?
no
id
0ff11c31-65fc-4609-991b-223d6813f681
date added to LUP
2020-02-20 14:18:45
date last changed
2020-05-31 06:53:49
@article{0ff11c31-65fc-4609-991b-223d6813f681,
  abstract     = {<p>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.</p>},
  author       = {Ma, Tao and Hoeffer, Charles A. and Capetillo-Zarate, Estibaliz and Yu, Fangmin and Wong, Helen and Lin, Michael T. and Tampellini, Davide and Klann, Eric and Blitzer, Robert D. and Gouras, Gunnar K.},
  issn         = {1932-6203},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {1--10},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease},
  url          = {http://dx.doi.org/10.1371/journal.pone.0012845},
  doi          = {10.1371/journal.pone.0012845},
  volume       = {5},
  year         = {2010},
}