β-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity

Sunamoto, Mie; Ohnishi, Kohta; Ichimori, Yuzo

doi:10.1016/0006-8993(96)00156-4

Cited by 161 publications

(101 citation statements)

References 52 publications

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“…Treatment of mesencephalic or cortical neuron-glia cultures with the same concentrations of Ab for 72 h did not produce detectable levels of NO, TNF-a and IL-1b. The lack of effect of Ab on the production of NO, TNF-a and IL-1b in our study is different from published reports (Ii et al 1996;Viel et al 2001). The difference is Fig.…”

Section: Discussioncontrasting

confidence: 99%

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Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

Qin

Liu

Cooper

et al. 2002

Journal of Neurochemistry

280

238

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The purpose of this study was to assess and compare the toxicity of b-amyloid (Ab) on primary cortical and mesencephalic neurons cultured with and without microglia in order to determine the mechanism underlying microglia-mediated Ab-induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron-glia cultures with Ab(1-42) over the concentration range 0.1-6.0 lM caused concentration-dependent neurotoxicity. High concentrations of Ab (6.0 lM for cortex and 1.5-2.0 lM for mesencephalon) directly injured neurons in neuron-enriched cultures. In contrast, lower concentrations of Ab (1.0-3.0 lM for cortex and 0.25-1.0 lM for mesencephalon) caused significant neurotoxicity in mixed neuron-glia cultures, but not in neuron-enriched cultures. Several lines of evidence indicated that microglia mediated the potentiated neurotoxicity of Ab, including the observations that low concentrations of Ab activated microglia morphologically in neuron-glia cultures and that addition of microglia to cortical neuron-glia cultures enhanced Ab-induced neurotoxicity. To search for the mechanism underlying the microglia-mediated effects, several proinflammatory factors were examined in neuron-glia cultures. Low doses of Ab significantly increased the production of superoxide anions, but not of tumor necrosis factor-a, interleukin-1b or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Ab toxicity in the presence of microglia. Inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Ab-induced neurotoxicity in neuron-glia mixed cultures. The role of NADPH oxidase-generated superoxide in mediating Ab-induced neurotoxicity was further substantiated by a study which showed that Ab caused less of a decrease in dopamine uptake in mesencephalic neuron-glia cultures from NADPH oxidase-deficient mutant mice than in that from wild-type controls. This study demonstrates that one of the mechanisms by which microglia can enhance the neurotoxicity of Ab is via the production of reactive oxygen species.

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Section: Discussioncontrasting

confidence: 99%

“…With higher concentrations of Ab (10 lM), significant amounts of NO and TNF-a were detected in our neuron-glia cultures (data not shown) as described in other reports (Ii et al 1996;Viel et al 2001). Taken together, the inhibition of microglia-generated superoxide might be the most efficient way to protect neurons from damage by Ab.…”

Section: Discussionsupporting

confidence: 84%

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

Qin

Liu

Cooper

et al. 2002

Journal of Neurochemistry

280

238

View full text Add to dashboard Cite

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“…Furthermore, although the reduction of total A␤ peptide concentration and attenuation of amyloid plaque deposition led to reduction of oxidative stress in the brain, the key form of A␤ peptide that results in the induction of such response is still to be determined. Our data are in agreement with the in vitro studies showing that both the monomeric 67 and fibrillar 68 forms of A␤ peptide play an important role in activating glial cells and producing oxidative stress responses.…”

Section: Discussionsupporting

confidence: 92%

Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

El‐Amouri

Zhu

et al. 2008

The American Journal of Pathology

167

132

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It is well established that the extracellular deposition of amyloid ␤ (A␤) peptide plays a central role in the development of Alzheimer's disease (AD). Therefore, either preventing the accumulation of A␤ peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant A␤ peptide-degrading enzyme in the brain; NEP becomes inactivated and down-regulated during both the early stages of AD and aging. In this study, we investigated the effect of human (h)NEP gene transfer to the brain in a mouse model of AD before the development of amyloid plaques, and assessed how this treatment modality affected the accumulation of A␤ peptide and associated pathogenetic changes (eg, inflammation, oxidative stress, and memory impairment). Overexpression of hNEP for 4 months in young APP/⌬PS1 double-transgenic mice resulted in reduction in A␤ peptide levels, attenuation of amyloid load, oxidative stress, and inflammation, and improved spatial orientation. Moreover, the overall reduction in amyloidosis and associated pathogenetic changes in the brain resulted in decreased memory impairment by ϳ50%. These data suggest that restoring NEP levels in the brain at the early stages of AD is an effective strategy to prevent or attenuate disease progression. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a loss of neurons in discrete regions of the brain, particularly in the cortex and hippocampus.1,2 The neuronal loss is accompanied by extracellular deposition of A␤ peptide in a form of senile plaques and intracellular accumulation of neurofibrillary tangles made of a hyperphosphorylated form of the microtubule-associated protein tau.3 Clinically, AD is characterized by a gradual decline in cognition, and changes in behavior and personality including difficulty in reasoning, disorientation, and language problems. The exact cause of AD is not yet clear, but it is widely assumed that accumulation and aggregation of A␤ peptide is the initial trigger for a complex, multistep cascade that includes gliosis, inflammatory changes, oxidative stress, neuritic/ synaptic changes, tangle formation (microtubule changes), and neurotransmitter loss, leading to dementia. 4 Therefore, lowering the A␤ peptide levels in the brain would stop or delay the onset of AD. NEP as one of the A␤ peptide-degrading enzymes, has been reported to play a key role in regulating the level of A␤ peptide in the brain. 5,6 NEP [neprilysin, previously called CD10 or common acute lymphoblastic leukemia antigen (CALLA)] is a type II membrane metalloendopeptidase composed of ϳ750 residues (ϳ110 kDa) with an active site containing a zinc-binding motif (HEXXH) at the extracellular carboxyl terminal domain.7-10 NEP is capable of degrading the monomeric and (possibly) the oligomeric forms of A␤ peptide. 11,12 In recent years several reports have indicated that the soluble (eg, oligomeric) forms of A␤ peptide play a significant role in memory impairment and AD, [13][14][15] however, it is noteworthy t...

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“…Production of these factors by microglia after exposure to lipopolysaccharide (LPS), the human immunodeficiency virus-1 coat protein gp120, or ␤-amyloid has been well documented (Boje and Arora, 1992;Chao et al, 1992;Dawson et al, 1994;Ii et al, 1996;Kong et al, 1996). Furthermore, activation of microglia and subsequent production of proinflammatory and cytotoxic factors have been attributed to increased neurotoxicity in in vitro neuron-glia cultures treated with LPS, ␤-amyloid, or a combination of IL-1, TNF␣, and interferon-␥ (Chao et al, 1992;Dawson et al, 1994;Jeohn et al, 1998), suggesting that microglia-derived factors such as NO and TNF␣ are important mediators of inflammationmediated neurodegeneration.…”

Section: Abstract: Endotoxin; Lipopolysaccharide; Inflammation; Gliamentioning

confidence: 99%

Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

et al. 2000

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Inflammation in the brain has been increasingly associated with the development of a number of neurological diseases. The hallmark of neuroinflammation is the activation of microglia, the resident brain immune cells. Injection of bacterial endotoxin lipopolysaccharide (LPS) into the hippocampus, cortex, or substantia nigra of adult rats produced neurodegeneration only in the substantia nigra. Although LPS appeared to impact upon mesencephalic neurons in general, an extensive loss of dopaminergic neurons was observed. Analysis of the abundance of microglia revealed that the substantia nigra had the highest density of microglia. When mixed neuron-glia cultures derived from the rat hippocampus, cortex, or mesencephalon were treated with LPS, mesencephalic cultures became sensitive to LPS at a concentration as low as 10 ng/ml and responded in a dose-dependent manner with the production of inflammatory factors and a loss of dopaminergic and other neurons. In contrast, hippocampal or cortical cultures remained insensitive to LPS treatment at concentrations as high as 10 g/ml. Consistent with in vivo observations, mesencephalic cultures had fourfold to eightfold more microglia than cultures from other regions. The positive correlation between abundance of microglia and sensitivity to LPS-induced neurotoxicity was further supported by the observation that supplementation with enriched microglia derived from mesencephalon or cortex rendered LPS-insensitive cortical neuron-glia cultures sensitive to LPS-induced neurotoxicity. These data indicate that the region-specific differential susceptibility of neurons to LPS is attributable to differences in the number of microglia present within the system and may reflect levels of inflammation-related factors produced by these cells.

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β-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity

Cited by 161 publications

References 52 publications

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

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