Interplay of Oxidative Stress and Inflammatory Genes in Alzheimer’s Disease Pathogenesis

Abstract

Neurodegenerative disorders (ND) are defined as a range of pathological conditions that lead to gradual and progressive neuronal loss and synapse loss in specific regions of the brain, resulting in dysfunction and irreversible changes in the central nervous system. Alzheimer’s Disease (AD) is a chronic neurological condition characterised by memory loss, cognitive impairment, and behavioural disturbances that progressively worsen over time. Evidence indicates that oxidative stress and inflammation significantly contribute to the pathophysiology and development of AD. These pathogenic factors are tightly regulated at the molecular level by unique gene networks that control immunological responses, neuronal survival, and the metabolism of reactive oxygen species (ROS). Genes associated with oxidative stress involved in the pathogenesis of AD include ERF, FAR2, DDAH2, HBA2/HBA1, CYP4F12, ATP11A, PPP3CA, and TMEM70. Reduced expression levels or impaired functionality of these genes lead to ROS accumulation, causing lipid peroxidation, mitochondrial dysfunction, and neuronal damage in AD.

Furthermore, APOE4 genotypes, which are highly linked to oxidative stress in the brain, are recognised as susceptibility genes for both the pathophysiology and phenotype of AD. Unsurprisingly, neuroinflammation also plays a crucial role in the pathophysiology of AD. The six genes that are primarily responsible for inducing inflammation in AD are CR1, CLU, HLA-DRB5/DRB1, INPP5D, MEF2C, and TREM2. It has been proposed that CLU indirectly influences the production of inflammatory cytokines such as IL-6 and TNF-α. By promoting Aβ aggregation, regulating astrocyte and microglia-mediated Aβ clearance and complement activation, and inducing microglial activation, CLU appears to play a significant role in AD pathogenesis. MEF2 governs microglial proliferation, which may contribute to the inflammatory processes occurring in the cerebral tissues of AD patients. The relationship between mRNA expression levels and protein expression for many of these genes remains unclear. Further research is necessary to determine the potential of these novel biomarkers for assessing oxidative stress, neuroinflammation, and disease status in AD patients.