Tau Oxidation
Tau oxidation plays a pivotal role in the etiology of Alzheimer’s disease (AD)86,87. Numerous experimental models and investigations conducted in the human brain have demonstrated the pivotal involvement of oxidative stress in the process of neurodegeneration, particularly in the early stages of Alzheimer’s disease (AD).
Mitochondrial dysfunction has been closely linked with the occurrence of oxidative stress, thereby serving as an incipient stimulus for the generation of amyloid-beta, a pivotal protein implicated in the pathogenesis of Alzheimer’s disease (AD)88–90. Accumulation of amyloid-beta has been observed to accelerate oxidative stress and exacerbate mitochondrial dysfunction90–92.
Oxidative stress has been identified as a significant factor in the pathogenesis of neurofibrillary tangles and aberrant accumulation of hyperphosphorylated tau protein, which are prevalent in the cerebral cortex of individuals with Alzheimer’s disease (AD)90. The identification of fatty acid oxidative products has established a direct association between the mechanisms underlying oxidative stress and the genesis of neurofibrillary tangles90,93.
In tandem with other contributing factors such as the presence of okadaic acid, oxidative stress has been observed to result in tau hyperphosphorylation90,94. The hyperphosphorylation of tau protein is hypothesized to arise from the interplay between oxidative stress and tau protein kinases and phosphatases, namely GSK-3β and PP2A. Multiple studies have demonstrated that glycogen synthase kinase-3 beta (GSK-3β) activity is enhanced in response to oxidative stress.
The intricate relationship between oxidative stress and tau pathology is multifaceted and has significant importance in the development and progression of Alzheimer’s disease (AD). Oxidative stress perturbs the regular functioning of cellular mechanisms, thereby giving rise to generating harmful entities such as reactive oxygen species (ROS). ROS, in turn, inflict damage to neurons and actively participate in the initiation and progression of Alzheimer’s disease (AD). When subjected to hyperphosphorylation in the presence of oxidative stress, the tau protein exhibits alterations in its conformational structure, thereby facilitating its aggregation into neurofibrillary tangles. This phenomenon exacerbates neurodegeneration90,94.
Antioxidant defenses for applications in AD treatment have been explored. Antioxidant defenses vary among preventative measures, radical-scavengers, and de novo and repair enzymes. Preventative antioxidant measures include metal-chelating proteins, superoxide dismutase, and glutathione peroxidase. Radical scavenging antioxidants include vitamins C and E. Repair and de novo enzymes include DNA repair enzymes, lipase, and protease. Currently, the metal chelating agent, clioquinol, vitamin C, and vitamin E are undergoing extensive clinical trials and epidemiological studies to determine if the administration of these compounds can ameliorate the progression of AD. Furthermore, it is plausible to test the integrative treatment of the aforementioned antioxidant compounds with nanoparticles to investigate whether their efficacy can be enhanced with the benefits (e.g., increased blood-brain barrier penetration, higher bioaccumulation) of nanoparticle delivery systems.
The exploration of therapeutic strategies for Alzheimer’s disease (AD) has led researchers to focus on the intricate relationship between oxidative stress and the tau phosphorylation pathways. By targeting oxidative stress and its impact on these pathways, there is a promising opportunity to develop effective AD treatments. The amelioration of tau pathology and neurodegeneration in Alzheimer’s disease (AD) can be achieved by mitigating oxidative stress and restoring cellular antioxidant defenses. Further investigation is warranted to comprehensively understand the intricate mechanisms at play and cultivate efficacious therapeutic interventions that specifically address the process of tau oxidation in Alzheimer’s disease (AD).