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

Marzia Perluigi, Anna Picca, Elita Montanari, Riccardo Calvani, Federico Marini, Roberto Matassa, Antonella Tramutola, Alberto Villani, Giuseppe Familiari, Fabio Di Domenico, D. Allan Butterfield, Kenneth J. Oh, Emanuele Marzetti, Diletta Valentini, Eugenio Barone

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Pages (from-to)1498-1510
Number of pages13
JournalAlzheimer's and Dementia
Volume18
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
This work was supported by Jerome-Lejeune Foundation grant no. 1887-BE2019B to EB and MP; and a Fondi Ateneo grant funded by Sapienza University no. RM11715C77336E99 to EB and no. C26H15JT9X to MP. Open Access Funding provided by Universita degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.

Funding Information:
2019 (PI) Grant from Sapienza University of Rome “Progetti Grandi,” Project ID RG11916B87F55459 34.000,00 Euro. Payment made to Sapienza University

Funding Information:
2020 (PI) Grant from Sapienza University of Rome “Progetti Medi,” Project ID RM120172A3160B53 10.000,00 Euros. Payment made to Sapienza University

Funding Information:
The authors disclose that this work was supported by Jerome‐Lejeune Foundation grant no. 1887‐BE2019B to EB and MP; Fondi Ateneo grant funded by Sapienza University no. RM11715C77336E99 to EB and no. C26H15JT9X to MP; NIH grants no. R56AG055596 and AG060056 to DAB.

Funding Information:
D. Allan Butterfield was recipient of grants from the National Cancer Institute, NIH and the National Institute on Aging, NIH during the past 36 months. All grants payments were to the University of Kentucky

Funding Information:
This work was supported by Jerome‐Lejeune Foundation grant no. 1887‐BE2019B to EB and MP; and a Fondi Ateneo grant funded by Sapienza University no. RM11715C77336E99 to EB and no. C26H15JT9X to MP.

Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Keywords

  • Alzheimer's disease
  • Down syndrome
  • Hsa21
  • PTEN
  • cognitive dysfunction
  • insulin signaling
  • intellectual disability
  • mTOR
  • neurodegeneration
  • neurodevelopment
  • trisomy 21

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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