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

doi:10.1002/alz.12499

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 journal › Article › peer-review

32 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 pIRS1^Ser636, 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 pGSK3β^Ser9 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 language	English
Pages (from-to)	1498-1510
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	18
Issue number	8
DOIs	https://doi.org/10.1002/alz.12499
State	Published - Aug 2022

Bibliographical note

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

Funding

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. 2019 (PI) Grant from Sapienza University of Rome “Progetti Grandi,” Project ID RG11916B87F55459 34.000,00 Euro. Payment made to Sapienza University 2020 (PI) Grant from Sapienza University of Rome “Progetti Medi,” Project ID RM120172A3160B53 10.000,00 Euros. Payment made to Sapienza University 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. 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 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.

Funders	Funder number
Jerome-Lejeune Foundation	1887‐BE2019B
Universita degli Studi di Roma La Sapienza
National Institutes of Health (NIH)	AG060056, R56AG055596
U.S. Department of Health & Human Services \| NIH \| National Institute on Aging (U.S. National Institute on Aging)
National Childhood Cancer Registry – National Cancer Institute
Università degli Studi di Roma Unitelma Sapienza	RM11715C77336E99, RM120172A3160B53 10.000,00, RG11916B87F55459 34.000,00, C26H15JT9X

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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

Access to Document

10.1002/alz.12499

Cite this

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. (2022). Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles. Alzheimer's and Dementia, 18(8), 1498-1510. https://doi.org/10.1002/alz.12499

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

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.",

keywords = "Alzheimer's disease, Down syndrome, Hsa21, PTEN, cognitive dysfunction, insulin signaling, intellectual disability, mTOR, neurodegeneration, neurodevelopment, trisomy 21",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2022",

month = aug,

doi = "10.1002/alz.12499",

language = "English",

volume = "18",

pages = "1498--1510",

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Perluigi, M, Picca, A, Montanari, E, Calvani, R, Marini, F, Matassa, R, Tramutola, A, Villani, A, Familiari, G, Domenico, FD, Butterfield, DA, Oh, KJ, Marzetti, E, Valentini, D & Barone, E 2022, 'Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles', Alzheimer's and Dementia, vol. 18, no. 8, pp. 1498-1510. https://doi.org/10.1002/alz.12499

TY - JOUR

T1 - Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles

AU - Perluigi, Marzia

AU - Picca, Anna

AU - Montanari, Elita

AU - Calvani, Riccardo

AU - Marini, Federico

AU - Matassa, Roberto

AU - Tramutola, Antonella

AU - Villani, Alberto

AU - Familiari, Giuseppe

AU - Domenico, Fabio Di

AU - Butterfield, D. Allan

AU - Oh, Kenneth J.

AU - Marzetti, Emanuele

AU - Valentini, Diletta

AU - Barone, Eugenio

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Down syndrome

KW - Hsa21

KW - PTEN

KW - cognitive dysfunction

KW - insulin signaling

KW - intellectual disability

KW - mTOR

KW - neurodegeneration

KW - neurodevelopment

KW - trisomy 21

UR - https://www.scopus.com/pages/publications/85119666649

UR - https://www.scopus.com/pages/publications/85119666649#tab=citedBy

U2 - 10.1002/alz.12499

DO - 10.1002/alz.12499

M3 - Article

C2 - 34812584

AN - SCOPUS:85119666649

SN - 1552-5260

VL - 18

SP - 1498

EP - 1510

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 8

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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