Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Marzia Perluigi, Gilda Pupo, Antonella Tramutola, Chiara Cini, Raffaella Coccia, Eugenio Barone, Elizabeth Head, D. Allan Butterfield, Fabio Di Domenico

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128 Scopus citations


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 40. years. 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 40. years) 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.

Original languageEnglish
Pages (from-to)1144-1153
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number7
StatePublished - Jul 2014

Bibliographical note

Funding Information:
All authors state that they have no conflicts of interest. This work was partially supported by PRIN2009 to C.C. and a NIH grant to D.A.B. [ A6-05119 ]. Brain tissue was acquired by EH under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging Grant #NIH 1RO1HD064993-01 . Additional autopsy tissue was obtained from the UCI-ADRC (P50AG16573), from the UK ADC (P30AG28383) and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore, MD, contract HHSN275200900011C (N01HD90011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  • Akt
  • Autophagy
  • Insulin signaling
  • PI3K
  • Trisomy 21
  • mTOR

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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