The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders

Abstract

For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91^phox and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation-primarily superoxide anion (O₂^●-), although hydrogen peroxide (H₂O₂) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.

Keywords: Alzheimer’s disease; NADPH oxidases; amyloid beta; cerebral amyloid angiopathy; dementia; reactive oxygen species.

Figure 1

Oxidative stress and blood brain barrier (BBB) breakdown: Reactive oxygen species (ROS) accumulation as a result of NADPH oxidases (NOX) activation, trauma or aging results in the accumulation of Aβ-protein, inflammatory and immune responses. Aβ accumulation also results in cerebral amyloid angiopathy (CAA) that leads to the failure in Aβ clearance. Aβ deposits on the vessel walls result in vascular fragility, loss of endothelial junction proteins and microglial activation. Aβ also facilitates the expression the receptor for advanced glycation end products (RAGE) in microvascular endothelial cells, neurons and microglia. Activated microglial cells release superoxides and nitric oxides which have been shown to cause neuronal cell death and oxidative damage under pathological conditions which eventually result in breakdown of the BBB, neuronal degradation and dementia.