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Review
. 2008 Dec 3;9 Suppl 2(Suppl 2):S8.
doi: 10.1186/1471-2202-9-S2-S8.

NADPH oxidase as a therapeutic target in Alzheimer's disease

Michelle L Block  1
Affiliations
Review

NADPH oxidase as a therapeutic target in Alzheimer's disease

Michelle L Block. BMC Neurosci. .

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 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.

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Figures

Figure 1
Figure 1
Microglia-mediated neuron damage. Microglia activation has been implicated in the progressive nature of Alzheimer's disease. 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 also 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. Although all forms of Aβ have yet to be tested in detail, NADPH oxidase (also called phagocytic oxidase (PHOX)) has been implicated as a key mechanism through which microglia damage neurons in response to Aβ and neuron damage/death. This figure is modified from Block et al. [3]. NO, nitric oxide; PGE2, prostaglandin E2; TNF, tumor necrosis factor.
Figure 2
Figure 2
NADPH oxidase inhibition targets deleterious microglial activation. Increasing evidence points to NADPH oxidase (also called phagocytic oxidase (PHOX)) as a critical mechanism of microglia-mediated neuron damage. Traditional anti-inflammatory approaches focus on specific downstream targets, such as prostaglandin E2 (PGE2). However, 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. At present, small molecules, peptides, anti-inflammatory cytokines, and an antibiotic have been identified that inhibit microglial NADPH oxidase and are neuroprotective. Further research is warranted to discover the mechanisms through which these seemingly diverse compounds work and to identify more specific inhibitors of this key neurotoxic pathway. This figure is modified from Zhang et al. [82]. IL, interleukin; TNF, tumor necrosis factor.
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