Epigenetic Changes Driven by Oxidative Stress in the Aging Brain
That immune cells in an inflammatory environment produce a much greater amount of oxidizing molecules is one of the reasons why increased levels of chronic inflammation and oxidative stress tend to be linked in older individuals. Researchers here review this mechanism in the context of Alzheimer's disease, as a way in which inflammation can drive detrimental epigenetic changes in cell populations in the brain, as those changes are in a part a reaction to an environment of greater oxidative stress.
It is widely accepted that chronic neuroinflammation plays a role in the development of Alzheimer's disease (AD), although the specific mechanisms remain elusive. Chronic low-grade inflammation is a characteristic of ageing and systemic inflammation is associated with AD onset, and we have presented a multitude of studies that suggest an effector role for immune cells in AD pathology. The extent to which peripheral immune cells, such as neutrophils, can enter the brain remains unclear and is difficult to measure temporally, however signs of oxidative stress are evident and clearly contribute to the aetiology of AD. Sources of oxidative stress are abundant in AD and include dysfunctional mitochondria, neurons, and endothelial cells, but immune cells are emerging as an abundant and potentially modifiable source.
Microglia are specialised immune cells of myeloid lineage that reside chiefly in the central nervous system and comprise up to 15% of all cell types found in the brain. Their main function is surveillance and maintenance of the central nervous system through clearance of dead and dying cells, as well as plaques. Microglia express NOX, an enzyme that produces superoxide and results in the formation of a range of oxidant species. Immune cell-derived oxidants differ greatly in their specificity and reactivities and produce a range of radical and non-radical species that can influence a variety of cellular and molecular processes, but can also cause tissue injury.
Oxidative stress can alter neuronal health both by directly damaging the DNA and causing cell death but also in more subtle ways, through the manipulation of key cellular enzymes and cofactors that have the potential to modify the epigenetic regulation of the genes associated with Alzheimer's disease onset and progression. Further studies are required to explore the impact of immune-derived oxidants on DNA methylation profiles in the ageing brain with the aim of uncovering targeted immunomodulatory, epigenetic, or mitochondrial therapeutic agents in the treatment of AD. As the world's population ages, it will become increasingly important to find reliable biomarkers of oxidative stress in middle-aged humans, before the onset of age-related disease such as AD, with the ultimate goal of prolonging the health span of individuals as they age.