Abstract
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 β amyloid (Aβ) 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 Aβ 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-α, prostaglandin E2, and interleukin-1β). 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 (Aβ and neuron damage), offering hope in halting the progression of AD.
Highlights
Alzheimer's disease (AD) affects more than 4 million people in the United States [1] and an estimated 27 million are affected worldwide [2]
NADPH oxidase contributes to a large proportion of intracellular reactive oxygen species (ROS) in phagocytes in response to an immunological stimulus, where approximately 50% of the LPS-induced intracellular ROS increase in microglia is due to NADPH oxidase [54]
NADPH oxidase has been implicated in the neurotoxic response of microglia to neuronal damage
Summary
Alzheimer's disease (AD) affects more than 4 million people in the United States [1] and an estimated 27 million are affected worldwide [2]. Microglia can become deleteriously activated in response to disease-specific stimuli (amyloid-β (Aβ) oligomers, Aβ fibrils, and senile plaques) to produce a catalogue of factors, such as reactive oxygen species and cytokines that are toxic to neurons. In addition to disease-specific pro-inflammatory stimuli, neuronal damage/death can activate microglia to produce these toxic factors. This continual and self-perpetuating cycle of neuronal damage/death followed by microglial activation is commonly referred to as reactive microgliosis and may be an underlying mechanism of the progressive nature of diverse neurodegenerative diseases, including Alzheimer's disease. Targeting NADPH oxidase inhibits the global pro-inflammatory response further upstream in the process of neurotoxic microglial activation and is able to inhibit a broad spectrum of cytokines, nitric oxide, and reactive oxygen species to confer neuroprotection.
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