Activation of NADPH Oxidase in Alzheimer's Disease Brains

223

229

Overproduction of the amyloid ␤ (A␤) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of A␤ on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by A␤. Thus, the free-radical production and the associated alterations in vasoregulation induced by A␤ are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91 phox ). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91 phox . The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91 phox -containing NADPH oxidase is the critical link between A␤ and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Park¹,

Anrather²,

Zhou³

et al. 2005

223

229

“…We have recently found that the plasmalemmal NADPH oxidase, an enzyme expressed predominantly in neutrophils and macrophages (for review, see Droge, 2002), is expressed also in astrocytes (Shimohama et al, 2000;A. Abramov and J. Jacobson, unpublished observations).…”

Section: Sources Of ␤A-induced Ros: a Role For The Nadph Oxidasementioning

confidence: 99%

β-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase

Abramov

Canevari²,

Duchen³

2004

538

372

␤-Amyloid (␤A) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of ␤A-induced neuronal death. ␤A causes a loss of mitochondrial potential in astrocytes but not in neurons. The mitochondrial response consists of Ca 2ϩ -dependent transient depolarizations superimposed on a slow collapse of potential. The slow response is both prevented by antioxidants and, remarkably, reversed by provision of glutamate and other mitochondrial substrates to complexes I and II. These findings suggest that the depolarization reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. Inhibition of NADPH oxidase by diphenylene iodonium or 4-hydroxy-3-methoxy-acetophenone blocks ␤A-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents ␤A-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of ␤A-induced neurodegeneration.

“…Neurons are protected by pharmacological inhibition (Qin et al, 2002;Abramov et al, 2003) or genetic modification of the NADPH oxidase (Block et al, 2006), supporting a neurotoxic role for NADPH oxidase-derived ROS . Because NADPH oxidase-derived ROS and resultant oxidative stress are strongly implicated in the pathogenesis of AD (Shimohama et al, 2000;Wilkinson and Landreth, 2006;Park et al, 2008), these processes and their mechanisms clearly represent attractive therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

“…Both NADPH oxidase and CLIC1 are upregulated in the AD brain (Shimohama et al, 2000;Parachikova et al, 2007) and expression of both increases in microglia in response to A␤ in vitro (Bianca et al, 1999;Novarino et al, 2004). CLIC1 blockade limits A␤-induced microglial-mediated neurotoxicity after 24 h (Novarino et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

CLIC1 Function Is Required for β-Amyloid-Induced Generation of Reactive Oxygen Species by Microglia

Milton¹,

Abeti²,

Averaimo³

et al. 2008

129

131

The Alzheimer's disease (AD) brain is characterized by plaques containing ␤-amyloid (A␤) protein surrounded by astrocytes and reactive microglia. Activation of microglia by A␤ initiates production of reactive oxygen species (ROS) by the plasmalemmal NADPH oxidase; the resultant oxidative stress is thought to contribute to neurodegeneration in AD. We have previously shown that A␤ upregulates a chloride current mediated by the chloride intracellular channel 1 (CLIC1) protein in microglia. We now demonstrate that A␤ promotes the acute translocation of CLIC1 from the cytosol to the plasma membrane of microglia, where it mediates a chloride conductance. Both the A␤ induced Cl Ϫ conductance and ROS generation were prevented by pharmacological inhibition of CLIC1, by replacement of chloride with impermeant anions, by an anti-CLIC1 antibody and by suppression of CLIC1 expression using siRNA. Thus, the CLIC1-mediated Cl Ϫ conductance is required for A␤-induced generation of neurotoxic ROS by microglia. Remarkably, CLIC1 activation is itself dependent on oxidation by ROS derived from the activated NADPH oxidase. We therefore propose that CLIC1 translocation from the cytosol to the plasma membrane, in response to redox modulation by NADPH oxidase-derived ROS, provides a feedforward mechanism that facilitates sustained microglial ROS generation by the NAPDH oxidase.