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Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease
Open accessAbstract
BACKGROUND: Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined. METHODOLOGY/PRINCIPAL FINDINGS: We used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Abeta(42), a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Abeta(42) levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Abeta and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Abeta. CONCLUSIONS/SIGNIFICANCE: Our data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.
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“Some studies have suggested that inhibition of mTOR activity may lead to cognitive improvement in mouse models of AD [54].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [54]
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“While rapamycin itself is not a strong inducer of autophagy compared to mTOR kinase inhibitors 53, the effects of rapamycin on the pathology of mouse models of Alzheimer’s disease has been attributed in part to increased autophagy 79,80.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [80]
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Metadata
- Authors
- Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., Richardson, A., Strong, R., & Galvan, V.
- Affiliations
- Buck Institute for Research on Aging (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, San Francisco (US)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-04-01
- Volume
- 5
- Issue
- 4
- Pages
- e9979
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2848616
- OpenAlex
- W2037653131
- Cited by
- 1,033
- References
- 52
- Citations by year
- 2026: 46 · 2025: 50 · 2024: 41 · 2023: 63 · 2022: 61 · 2021: 75 · 2020: 91 · 2019: 82 · 2018: 72 · 2017: 57 · 2016: 68 · 2015: 75 · 2014: 72 · 2013: 62 · 2012: 58
- FWCI
- 39.00
- Type
- journal article
- Language
- en
- Update notices
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs
- Alzheimer's Association (NIRG-DDC-120433)
- Buck Institute for Research on Aging
- University of Texas Health Science Center at San Antonio
- National Institute on Aging (P30AG13319, P30AG013319, U01AG022307)
- National Cancer Institute (R01CA126792)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- rapamycin, mTOR inhibition, Alzheimer's disease, amyloid-beta 42, cognitive impairment, autophagy, lifespan extension, neuroprotection, therapeutic target
- MeSH terms
- Aging, Alzheimer Disease, Animals, Autophagy, Cognition Disorders, Disease Models, Animal, Immunosuppressive Agents, Signal Transduction, Amyloid beta-Peptides, Sirolimus, Mice, TOR Serine-Threonine Kinases
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