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Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease
Open accessAbstract
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.
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“mTOR activity, which is increased by Reelin signaling (92), is lower in AD mice (93).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [93]
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Metadata
- Authors
- Ma, T., Hoeffer, C. A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M. T., Tampellini, D., Klann, E., Blitzer, R. D., & Gouras, G. K.
- Affiliations
- Weill Cornell Medicine (US)
- New York University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Gouras, Gunnar K.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-20
- Volume
- 5
- Issue
- 9
- Pages
- e12845
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2942840
- OpenAlex
- W2071279551
- Cited by
- 262
- References
- 52
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 7 · 2023: 13 · 2022: 13 · 2021: 20 · 2020: 26 · 2019: 10 · 2018: 11 · 2017: 14 · 2016: 18 · 2015: 17 · 2014: 30 · 2013: 23 · 2012: 22
- FWCI
- 13.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Communities in ADDI (University of the Basque Country) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Hispana (submittedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institutes of Health (N S03400 7, AG‐09464, AG28174)
- National Institute on Aging (R01AG027140, AG09464, R01AG020729, K02AG028174, AG28174, AG027140, P01AG009464)
- National Institute of General Medical Sciences (R01GM054508, GM-054508)
- National Institute of Neurological Disorders and Stroke (R37NS034007, R01NS034007, R29NS034007, NS-034007)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- mTOR signaling, Alzheimer's disease, synaptic plasticity, amyloid-beta, amyloid-beta 42, long-term potentiation, glycogen synthase kinase-3, GSK-3 inhibitors, FKBP12, hippocampus, synaptic dysfunction, intraneuronal amyloid-beta
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Humans, Mice, Inbred C57BL, Neuronal Plasticity, Peptide Fragments, Synapses, Signal Transduction, Amyloid beta-Peptides, Long-Term Potentiation, Mice, TOR Serine-Threonine Kinases
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