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

Biochim Biophys Acta. 2014 Jul;1842(7):1144-53. doi: 10.1016/j.bbadis.2014.04.007. Epub 2014 Apr 13.

Abstract

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 40years. 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 40years) 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.

Keywords: Akt; Autophagy; Insulin signaling; PI3K; Trisomy 21; mTOR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Autophagy / physiology
  • Case-Control Studies
  • DNA-Binding Proteins
  • Down Syndrome / enzymology
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology*
  • Female
  • Frontal Lobe / metabolism*
  • Frontal Lobe / pathology*
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System
  • Male
  • Middle Aged
  • Muscle Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Young Adult
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • DNA-Binding Proteins
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • RCAN1 protein, human
  • tau Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt