NADPH oxidase as a therapeutic target in Alzheimer's disease.
At present, available treatments for Alzheimer's disease (AD) are largely unable to halt disease progression. Microglia, the resident macrophages in the brain, are strongly implicated in the pathology and progressively degenerative nature of AD. Specifically, microglia are activated in response to both beta amyloid (Abeta) and neuronal damage, and can become a chronic source of neurotoxic cytokines and reactive oxygen species (ROS). NADPH oxidase is a multi-subunit enzyme complex responsible for the production of both extracellular and intracellular ROS by microglia. Importantly, NADPH oxidase expression is upregulated in AD and is an essential component of microglia-mediated Abeta neurotoxicity. Activation of microglial NADPH oxidase causes neurotoxicity through two mechanisms: 1) extracellular ROS produced by microglia are directly toxic to neurons; 2) intracellular ROS function as a signaling mechanism in microglia to amplify the production of several pro-inflammatory and neurotoxic cytokines (for example, tumor necrosis factor-alpha, prostaglandin E2, and interleukin-1beta). The following review describes how targeting NADPH oxidase can reduce a broad spectrum of toxic factors (for example, cytokines, ROS, and reactive nitrogen species) to result in inhibition of neuronal damage from two triggers of deleterious microglial activation (Abeta and neuron damage), offering hope in halting the progression of AD.
Block
Michelle L
ML
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA 23298, USA. Block@vcu.edu
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008954:Models, Biological; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016207:Cytokines; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases