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Cited by 35Down syndrome and intellectual disability researchExtracellular vesicles in diseaseAlzheimer's disease research and treatments

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal‐derived extracellular vesicles

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Perluigi, Marzia, Picca, Anna, Montanari, Elita, Calvani, Riccardo, Marini, Federico, Matassa, Roberto, Tramutola, Antonella, Villani, Alberto +7 more·2022·Alzheimer's & Dementia
DOI 10.1002/alz.12499PMC PMC10131479
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Abstract

Abstract Introduction Intellectual disability, accelerated aging, and early‐onset Alzheimer‐like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. Methods Neuronal‐derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. Results nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found. Conclusions The alteration of the insulin‐signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.

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  • Upstream activators of the mTORC1/2 complexes include PI3K, Akt, INS, and IGF1.

    “Upstream activators of the mTORC1/2 complexes include phosphatidylinositol 3‐kinase (PI3K), protein kinase B (Akt), insulin (INS), and insulin‐like growth factor 1 (IGF1). 9”

    From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [9]

    The Discussion describes insulin/PI3K signaling, identifies mTOR as a downstream target of Akt, and says insulin promotes activation of the Akt/mTOR axis. It does not identify IGF1 as an upstream activator or establish the claim separately for both mTORC1 and mTORC2. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • INS-independent mTOR hyperactivation leads to excessive degradation of IRS1, resulting in brain INS resistance.

    “Moreover, the occurrence of INS‐independent mTOR hyperactivation leads to excessive degradation of IRS1, resulting in brain INS resistance 9 , 14”

    From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [9]

    The Discussion (page unavailable) proposes that mTOR/p70S6K hyperactivation may cause IRS1 inhibition in children with Down syndrome and links chronic mTOR hyperactivation to reduced insulin sensitivity. It identifies IRS1 phosphorylation and inhibition, not excessive IRS1 degradation; it also does not establish that mTOR hyperactivation is independent of insulin signaling. The claim states the proposed causal link more definitively than the paper does. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Our 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”

    From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [9]

    The Discussion reports IRS1 inhibition alongside increased Akt, mTOR, and P70S6K activation in neuronal-derived vesicles from children with Down syndrome. It also cites prior findings of aberrant mTOR signaling in people with Down syndrome with and without AD, but it does not establish the full axis with IRS1 inhibition specifically in humans with DS-AD. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 51

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Authors
Perluigi, M., Picca, A., Montanari, E., Calvani, R., Marini, F., Matassa, R., Tramutola, A., Villani, A., Familiari, G., Domenico, F. D., Butterfield, D. A., Oh, K. J., Marzetti, E., Valentini, D., & Barone, E.
Affiliations
  • Department of Biochemical Sciences “A. Rossi‐Fanelli” Sapienza University of Rome Rome Italy
  • Agostino Gemelli University Polyclinic (IT)
  • Institute of Pharmaceutical Sciences (CH)
  • Sapienza University of Rome (IT)
  • Bambino Gesù Children's Hospital (IT)
  • University of Kentucky (US)
  • Bio-Rad (United States) (US)
  • Università Cattolica del Sacro Cuore (IT)
Corresponding author
Barone, Eugenio
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2021-11-23
Volume
18
Issue
8
Pages
1498-1510
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.12499
PMC
PMC10131479
OpenAlex
W3216156101
Cited by
35
References
64
Citations by year
2026: 7 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 5 · 2021: 1
FWCI
4.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by-nc)
  • Iris (Roma Tre University) (submittedVersion)
  • Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc)
  • ETH Zürich Research Collection
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Down syndrome, insulin signaling
MeSH terms
Extracellular Vesicles, Adolescent, Alzheimer Disease, Child, Down Syndrome, Humans, Infant, Insulin, Intellectual Disability, TOR Serine-Threonine Kinases

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