Subacute NO generation induced by Alzheimer's β‐amyloid in the living brain: reversal by inhibition of the inducible NO synthase

Ishii, Kazuhiro; Muelhauser, F.; Liebl, Ulrike; Picard, Martin; Kühl, Sandra; Penke, Botond; Bayer, Thomas A.; Wießler, Manfred; Hennerici, M.; Beyreuther, Konrad; Hartmann, Thomas; Faßbender, Klaus

doi:10.1096/fj.99-0786com

Cited by 37 publications

(27 citation statements)

References 34 publications

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“…Primary murine microglia of Tlr4-defective C3H/HeJ and wild-type C3H/HeN mice were prepared as described elsewhere [36]. Briefly, brains of newborn mice day 1-3 were isolated and meninges removed.…”

Section: Cellular Stimulation With Aβmentioning

confidence: 99%

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Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease

Walter

Letièmbre

Liu

et al. 2007

Cell Physiol Biochem

465

357

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Microglial activation is a key feature in Alzheimer’s disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFα and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer’s disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer’s disease.

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Section: Cellular Stimulation With Aβmentioning

confidence: 99%

“…Detection levels were 15.6 pg/ml for IL-6 and 31.25 pg/ml for TNFα. Nitrite, the stable metabolite of NO, was measured by the Grieß assay [36] after 24 and 48 h. Detection level was 1.5 µM.…”

Section: Cellular Stimulation With Aβmentioning

confidence: 99%

Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease

Walter

Letièmbre

Liu

et al. 2007

Cell Physiol Biochem

465

357

View full text Add to dashboard Cite

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“…The ability of A to elicit NO release and oxidative stress is controversial (Forloni et al, 1997;Hu et al, 1998;Meda et al, 1999;Ishii et al, 2000). Some results indicate that A triggers production of NO and inflammatory molecules in microglia and astrocytes in vitro (Meda et al, 1995;Malchiodi-Albedi et al, 2001;Rogers et al, 2002).…”

Section: Participation Of Glial Cells In Neurodegenerative Diseasesmentioning

confidence: 99%

Glial cell dysregulation: a new perspective on Alzheimer disease

2007

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Alzheimer disease (AD) is a major cause of dementia. Several mechanisms have been postulated to explain its pathogenesis, beta-amyloid (A beta toxicity, cholinergic dysfunction, Tau hyper-phosphorylation, oxidative damage, synaptic dysfunction and inflammation secondary to senile plaques, among others. Glial cells are the major producers of inflammatory mediators, and cytotoxic activation of glial cells is linked to several neurodegenerative diseases; however, whether inflammation is a consequence or the cause of neurodegeneration is still unclear. I propose that inflammation and cellular stress associated with aging are key events in the development of AD through the induction of glial dysfunction. Dysregulated inflammatory response can elicit glial cell activation by compounds which are normally poorly reactive. Inflammation can also be the major cause of defective handling of A beta and the amyloid precursor protein (APP). Here I review evidence that support the proposal that dysfunctional glia and the resulting neuroinflammation can explain many features of AD. Evidence supports the notion that damage caused by inflammation is not only a primary cause of neurodegeneration but also an inducer for the accumulation of A beta in AD. Dysfunctional glia can result in impaired neuronal function in AD, as well as in many progressive neurodegenerative disorders. We show that microglial cell activation is enhanced under pro-inflammatory conditions, indicating that glial cell responses to A beta related proteins can be critically dependent on the priming of glial cells by pro-inflammatory factors.

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“…In vivo microdialysis was performed as previously described. 17 Rats were anesthetized with a mixture of 2% fentanyl (6 mg/kg body wt IP) plus medetomidin (0.3 mg/kg body wt IP) and placed in a stereotaxic apparatus. Thereafter, the dura was exposed through a 2-mm hole in the skull, and the microdialysis probe was inserted in the striatum.…”

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confidence: 99%

Subacute But Not Acute Generation of Nitric Oxide in Focal Cerebral Ischemia

Faßbender

Fatar

Ragoschke

et al. 2000

Stroke

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Background and Purpose-Excessive release of nitric oxide (NO) has been implicated in the pathophysiology of neurodegeneration in ischemic stroke. We compared intracerebral release of indicators of NO generation at the acute and subacute stages of transient focal cerebral ischemia. Methods-In vivo microdialysis in the rat striatum was performed at the acute (first hours) and subacute (after 24 or 48 hours) stages of cerebral ischemia or sham operation to monitor intracerebral release of the stable NO metabolites nitrite and nitrate. Results-Whereas only a nonsignificant trend toward increased release of these NO metabolites was evidenced in acute cerebral ischemia, a significant NO generation was observed subacutely, 48 hours after induction of cerebral ischemia. Aminoguanidine, a selective inhibitor of inducible NO synthase, suppressed this delayed release of nitrite and nitrate. Conclusions-Whereas these observations do not support a major NO generation in acute cerebral ischemia, they indicate an inducible NO synthase-dependent NO generation predominantly at the subacute phase of ischemic neurodegeneration. Therefore, NO generation may play a pathophysiological role in delayed ischemic neurodegeneration. (Stroke. 2000;31:2208-2211.)Key Words: cerebral ischemia, focal Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ rats W hereas in low concentrations (nanomolar range), nitric oxide (NO) plays a physiological role in neuronal signaling, in high concentrations (micromolar range) this molecule is enormously cytotoxic. 1 The production of NO, itself a free radical, promotes tissue injury, eg, by reaction with superoxide anion to produce the extremely toxic peroxynitrite or by interaction with proteins, transition metals, and iron-sulfur-containing or heme-containing compounds. 2,3 Excessive NO generation has been implicated in ischemic neurodegeneration 4,5 and is currently intensely studied as a therapeutic target in ischemic stroke. 5,6 The rapidly decaying gas NO cannot be detected directly. However, changes in concentrations of the stable NO oxidation products nitrite and nitrate allow estimation of NO generation. 7 Recently, extracellular release of NO metabolites in the central nervous system has been reported in acute global 8 -11 or focal 12,13 cerebral ischemia with the use of in vivo microdialysis. This technique allows repeated sampling of brain tissue perfusate in the same freely moving rat. 14 The results of these studies were conflicting since they showed decreased or increased concentrations of NO metabolites for minutes or hours. More importantly, whereas formation of NO metabolites has been monitored with this technique only in the acute stage of focal cerebral ischemia, there is, to our knowledge, no information about a possible NO generation in the subacute phase (ie, beyond 24 hours). This uncertainty clearly contrasts with the general belief that NO is a key molecule in the pathogenesis of ischemic neurodegeneration and represents an important therapeutic target in ischemic stroke. 5 In this study we...

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Subacute NO generation induced by Alzheimer's β‐amyloid in the living brain: reversal by inhibition of the inducible NO synthase

Cited by 37 publications

References 34 publications

Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease

Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease

Glial cell dysregulation: a new perspective on Alzheimer disease

Subacute But Not Acute Generation of Nitric Oxide in Focal Cerebral Ischemia

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