Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease
(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
- 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
- publishing date
- 2010-09-20
- 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 (PLoS)
- external identifiers
-
- scopus:77958465822
- pmid:20862226
- 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
- 2024-05-29 09:29:03
@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 (PLoS)}}, 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}}, }