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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The oxidatively modified proteins in Down syndrome include proteins linked to altered glucose metabolism, mTOR signaling with inhibited autophagy and increased insulin resistance, and the proteostasis network.
“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]
The Discussion (page unavailable) reports oxidative modification of proteins in the proteostasis network, including components of protein-degradation pathways. The Conclusion (page unavailable) links mTOR hyperactivation to reduced autophagy and decreased IRS1 activity, which can lead to insulin resistance. It does not identify oxidatively modified proteins associated with altered glucose metabolism or establish that the mTOR–insulin-resistance findings concern oxidatively modified proteins. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmTOR activation is abnormally high in the brains of DS mouse models and in DS fibroblasts.
“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
The Results section (mTOR activation and inhibition of autophagosome formation; page unavailable) reports increased mTOR phosphorylation in Down syndrome brain tissue compared with age-matched controls. The Methods identify the tissue as frontal cortex from people with Down syndrome, not mouse models. The Discussion mentions altered Akt phosphorylation in DS mouse models, but does not establish increased mTOR activation in their brains. The fibroblast claim is attached to a different citation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOur findings support a hyperactivated AKT/mTOR/p70S6K axis with IRS1 inhibition in humans with DS-AD.
“Our findings support a hyperactivated AKT/mTOR/p70S6K axis with IRS1 inhibition in humans with DS‐AD. 7 , 9 , 59”
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Self-citationMammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration
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Aberrant insulin signaling in Alzheimer's disease: current knowledge
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Self-citationMetabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease
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Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)
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Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer׳s disease
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Self-citationIdentification of a DNA methylation signature in blood cells from persons with Down Syndrome
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Amyloid-beta and tau protein beyond Alzheimer’s disease
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Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome
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Self-citationBiliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease
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Self-citationTargeting Mitochondria in Alzheimer Disease: Rationale and Perspectives
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Self-citationTargeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies.
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The burden of trisomy 21 disrupts the proteostasis network in Down syndrome
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The Implications of Autophagy in Alzheimer’s Disease
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Perspectives on Oxidative Stress in Alzheimer’s Disease and Predictions of Future Research Emphases
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Self-citationDown Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro
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Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism
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Self-citationCathepsin D as a therapeutic target in Alzheimer’s disease
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Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2
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Self-citationRapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome
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Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer’s Disease Pathology
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Molecular Mechanism of Autophagy: Its Role in the Therapy of Alzheimer’s Disease
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Self-citationPoly-ubiquitin profile in Alzheimer disease brain
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Self-citationModeling Down syndrome in animals from the early stage to the 4.0 models and next
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Consequences of chromosome gain: A new view on trisomy syndromes
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Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules
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Copine1 regulates neural stem cell functions during brain development
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Astrocytes in Down Syndrome Across the Lifespan
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Self-citationRvE1 treatment prevents memory loss and neuroinflammation in the Ts65Dn mouse model of Down syndrome
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The role of hypernitrosylation in the pathogenesis and pathophysiology of neuroprogressive diseases
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Developmental Neuropathology and Neurodegeneration of Down Syndrome: Current Knowledge in Humans
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Entorhinal cortex stimulation induces dentate gyrus neurogenesis through insulin receptor signaling
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Insulin resistance in Alzheimer disease: Is heme oxygenase-1 an Achille's heel?
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Self-citationLife and death in the hippocampus: What's bad?
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The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome
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Ketamine: A Neglected Therapy for Alzheimer Disease
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Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?
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Bridging the age spectrum of neurodegenerative storage diseases
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Redox imbalance and metabolic defects in the context of Alzheimer disease
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Self-citationEndosome Dysregulation in Down Syndrome: A Potential Contributor to Alzheimer Disease Pathology
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Self-citationAKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome
Peeters, D., Pico‐Knijnenburg, I., Wieringa, D., Rad, M., Cuperus, R., Ruige, M., Froeling, F. M. J. A., Zijp, G. W., van der Burg, M., & Driessen, G. J. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.724436 · Cited by 17 · see citing works
Kaur, G., Gauthier, S. A., Pérez‐González, R., Pawlik, M., Singh, A. B., Cosby, B., Mohan, P. S., Smiley, J. F., & Levy, E. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.08.025 · Cited by 17 · see citing works
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Ren, J., Xiang, B., Xueling, L., Han, X., Yang, Z., Zhang, M., & Zhang, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e36470 · Cited by 16 · see citing works
Urbano‐Gámez, J. D., Benito, I., Casañas, J. J., & Montesinos, M. L. (2021) · Molecular Brain · doi:10.1186/s13041-021-00795-6 · Cited by 16 · see citing works
- 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 · 2012: 1
- 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
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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