The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index.
Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain
Open accessAbstract
Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.
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“These oxidatively modified, and likely dysfunctional, proteins include ones associated with altered glucose metabolism, mTOR signaling (including inhibited autophagy and increased insulin resistance), and the proteostasis network42,61,62,65,66.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [61]
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“the abnormally high level of mTOR activation seen in the brains of DS mouse models (Iyer et al., 2014;Perluigi et al., 2014) and in DS fibroblasts (Bordi et al., manuscript submitted)”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Perluigi et al., 2014
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“Our findings support a hyperactivated AKT/mTOR/p70S6K axis with IRS1 inhibition in humans with DS‐AD. 7 , 9 , 59”
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“Higher mTORC1/S6K activity in muscle of older mice, rats and humans is associated with sarcopenia 97–101, and in brain is associated with Alzheimer’s disease 101–105.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [103]
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Cites
Mechanism of activation of protein kinase B by insulin and IGF‐1.
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Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy
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Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study
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“This signaling cascade is finely regulated by a negative feedback mechanism that suppresses Akt activity in case of a permanent activation of mTOR/p70S6K signal [52] [53] [54].”
Bomfim, T. R., Forny‐Germano, L., Sathler, L. B., Brito‐Moreira, J., Houzel, J., Decker, H., Silverman, M. A., Kazi, H., Melo, H. M., McClean, P. L., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci57256 · Cited by 849
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Research works printed but not linked: 1
- Lovestone, 1997, The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes, Neuroscience, 78, 309
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Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954
Self-citationHeras-Sandoval, D., Pérez-Rojas, J. M., Hernández-Damián, J., & Pedraza-Chaverri, J. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.08.019 · Cited by 1,091
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Self-citationButterfield, D. A., Di Domenico, F., & Barone, E. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.06.010 · Cited by 402
Self-citationMolecular neurobiology of mTOR
Switon, K., Kotulska, K., Janusz, A., Zmorzyńska, J., & Jaworski, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.11.017 · Cited by 405
Metadata
- Authors
- Perluigi, M., Pupo, G., Tramutola, A., Cini, C., Coccia, R., Barone, E., Head, E., Butterfield, D. A., & Di Domenico, F.
- Affiliations
- Sapienza University of Rome (IT)
- University of Kentucky (US)
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 1842
- Issue
- 7
- Pages
- 1144-1153
- ISSN
- 0925-4439 (ISSN-L)
- PMC
- PMC4062876
- OpenAlex
- W2158742765
- Cited by
- 155
- References
- 77
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 15 · 2023: 10 · 2022: 11 · 2021: 15 · 2020: 16 · 2019: 16 · 2018: 11 · 2017: 16 · 2016: 13 · 2015: 15 · 2014: 5
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- PRIN2009
- NIH (A6-05119)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging (1RO1HD064993-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Down syndrome, PI3K/AKT/mTOR pathway, Alzheimer's disease, frontal cortex, autophagy, IRS-1, GSK3β, RCAN1, tau phosphorylation, amyloid-beta, intellectual disability, dementia
- MeSH terms
- Adult, Alzheimer Disease, Autophagy, DNA-Binding Proteins, Down Syndrome, Female, Frontal Lobe, Humans, Male, Middle Aged, Muscle Proteins, Phosphorylation, Case-Control Studies, Amyloid beta-Peptides, tau Proteins, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Insulin Receptor Substrate Proteins, Young Adult, TOR Serine-Threonine Kinases
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