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

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.