Oxidative stress and mTOR in Down syndrome brain: Link to Alzheimer’s dysmetabolism, neuropathology, and possible therapies

Marzia Perluigi, Fabio Di Domenico, D. Allan Butterfield

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

The complexity of Down Syndrome (DS) neurodegeneration involves multiple molecular mechanisms, similar to what observed in Alzheimer’s disease (AD) brain, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylation in neurofibrillary tangles. Intriguingly, several trisomic genes in addition to being primarily linked to Aβ pathology are responsible for increased oxidative stress (OS) conditions. Indeed, growing studies support the notion that OS contributes to neurodevelopmental defects, neuronal dysfunction, as well as the accelerated aging phenotype of the DS population. Oxidative damage accumulates over the lifespan in parallel with the loss of function of the protein quality control (PQC) systems, including the ubiquitin-proteasome and autophagy. Considering that oxidative damage to proteins induces aggregation, the ability to remove toxic aggregates is essential to prevent neurodegeneration. However, we should consider that the activity of the PQC is compromised by oxidative modification of some of its components thus resulting in increased accumulation of oxidized/misfolded proteins. This scenario highlights that accumulation of oxidative damage together with impairment of protein clearance systems contributes to accelerate neurodegeneration in DS population ultimately resulting in early onset AD neuropathology and dementia.

Original languageEnglish
Title of host publicationThe Neurobiology of Aging and Alzheimer Disease in Down Syndrome
Pages75-96
Number of pages22
ISBN (Electronic)9780128188453
DOIs
StatePublished - Jan 1 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc. All rights reserved.

Keywords

  • Alzheimer’s disease
  • Amyloid beta
  • Autophagy
  • Down syndrome
  • mTOR
  • Oxidative stress
  • Tau

ASJC Scopus subject areas

  • Medicine (all)

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