The emerging role of NADPH oxidases (NOX) in Alzheimer's disease pathogenesis

Alzheimer's disease (AD) is a slow-progressing neurodegenerative disease, mainly characterized by the accumulation of amyloid beta (Aβ) plaques and intracellular hyperphosphorylated Tau protein, along with the generation of free radicals. In normal physiology free radicals play a promising role. However, the imbalance in the formation and clearance of the free radicals or reactive oxygen species/reactive nitrogen species (ROS/RNS) disrupts redox homeostasis, resulting in oxidative stress. Cellular disruption through the oxidation of lipids, proteins, and nucleic acids along with the disruption of the blood-brain barrier (BBB) integrity, and neuroinflammation are linked with AD pathogenesis. Albeit there are various ROS-generating sources, notably mitochondria, endoplasmic reticulum (ER), peroxisomes, NADPH oxidase (NOX), and several other oxidases, but out of all, the second most well-studied ROS-generating component after mitochondria is thought to be NOX. It is a multi-subunit enzyme family, activated by the phosphorylation of its cytosolic subunit, culminating in the production of superoxide (O₂^•-) anions. It comprises seven different isoforms, where NOX2 is the most studied isoform found to be the major source of ROS production in the brain. Therefore, inhibiting NOX-induced oxidative stress in the brain might be a promising therapeutic approach for AD. Thus, the current review enlightens the role of NOX in neurodegenerative AD progression, Aβ pathology and focusing on the therapeutic interventions by employing different phytochemicals as natural inhibitors and the synthetic inhibitors to combat the pathogenicity associated with NOX in the case of AD.