Dysfunction of the mTOR pathway is a risk factor for Alzheimer's disease
Open accessAbstract
Background: The development of disease-modifying therapies for Alzheimer’s disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors. We have documented the expression pattern of mTOR regulated genes in the frontal cortex of Alzheimer’s disease patients. We have also examined the functional integrity of mTOR signaling in peripheral lymphocytes in Alzheimer’s disease patients relative to healthy controls. Results: In the brain mTOR is seen to control molecular functions related to cell cycle regulation, cell death and several metabolic pathways. These downstream elements of the mTOR signaling cascade are deregulated in the brain of Alzheimer’s disease patients well before the development of pathology. This dysregulation of the mTOR downstream signaling cascade is not restricted to the brain but appears to be systemic and can be detected in peripheral lymphocytes as a reduced Rapamycin response. Conclusions: The dysfunction of the signaling pathways downstream of mTOR may represent a risk factor for Alzheimer’s disease and is independent of the ApoE status of the patients. We have also identified the molecular substrates of the beneficial effects of Rapamycin on the nervous system. We believe that these results can further inform the development of clinical predictive tests for the risk of Alzheimer’s disease in patients with mild cognitive impairment.
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mTORC1 and its downstream targets are hyperactive in human brains diagnosed with Alzheimer's disease.
“For example, mTORC1 and its downstream targets are hyperactive in human brains diagnosed with Alzheimer's disease (AD) (18 -20).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [20]
The Background (page unavailable) reports up-regulation of components downstream of mTORC1 in AD brains. It does not establish that mTORC1 itself is hyperactive; moreover, the Results section on advanced AD says most differentially expressed downstream genes changed in a direction consistent with mTOR inhibition. (LLM, conf=0.88)
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Tramutola, A., Triplett, J. C., Di Domenico, F., Niedowicz, D. M., Murphy, M. P., Coccia, R., Perluigi, M., & Butterfield, D. A. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13037 · Cited by 347 · see citing works
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“Dysregulation of mTOR signalling has even been suggested as an early event in AD pathogenesis [11, 12] with implications for tau pathology through decreased autophagy [9, 13–15].”
BackgroundSelf-citation
- Authors
- Yates, S. C., Zafar, A., Hubbard, P., Nagy, S., Durant, S., Bicknell, R., Wilcock, G., Christie, S., Esiri, M. M., Smith, A. D., & Nagy, Z.
- Affiliations
- University of Birmingham (GB)
- John Radcliffe Hospital (GB)
- University of Oxford (GB)
- Corresponding author
- Nagy, Zsuzsanna
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2013-05-08
- Volume
- 1
- Issue
- 1
- Pages
- 3-3
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC3776211
- OpenAlex
- W2156040202
- Cited by
- 76
- References
- 4
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 5 · 2021: 9 · 2020: 5 · 2019: 3 · 2018: 8 · 2017: 6 · 2016: 10 · 2015: 5 · 2014: 3
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Institute for Health and Care Research
- University of Birmingham
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, mTOR signaling, peripheral blood lymphocytes, cell cycle regulation, cell death, mild cognitive impairment, disease-modifying therapy
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Cell Cycle, Cells, Cultured, Female, Frontal Lobe, Humans, Lymphocytes, Male, Middle Aged, Risk Factors, Signal Transduction, Gene Expression, Sirolimus, Protein Kinase Inhibitors, TOR Serine-Threonine Kinases
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