Marzia Perluigi1, Anna Picca2, Elita Montanari3, Riccardo Calvani2, Federico Marini4, Roberto Matassa5, Antonella Tramutola1, Alberto Villani6, Giuseppe Familiari5, Fabio Di Domenico1, D Allan Butterfield7, Kenneth J Oh8, Emanuele Marzetti2,9, Diletta Valentini6, Eugenio Barone1. 1. Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Rome, Italy. 2. Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. 3. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Zurich, Switzerland. 4. Department of Chemistry, Sapienza University of Rome, Roma, Italy. 5. Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Section of Human Anatomy, Sapienza University of Rome, Rome, Italy. 6. Pediatric Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy. 7. Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA. 8. Bio-Rad Laboratories, Hercules, California, USA. 9. Università Cattolica del Sacro Cuore, Department of Geriatrics and Orthopedics, Rome, Italy.
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.
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.