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).