??-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon-gamma and "advanced glycation endproducts" in a mouse microglia cell line

Gasic-Milenkovic, Jovana; Dukić-Stefanović, Sladjana; Deuther‐Conrad, Winnie; nch, Gerald M

doi:10.1240/sav_gbm_2002_h_000162

Cited by 22 publications

(31 citation statements)

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“…While IL-1β has been shown to increase the synthesis [96] and processing [97] of amyloid precursor protein (APP) favoring the release of amyloid peptide fragments, Aβ stimulates microglial activation in vitro [29,41,98] and in vivo [29,[99][100][101][102] and this is accompanied by increased release of cytokines including IL-1β [29,100,102]. These findings suggest that a spiral of damaging events, involving accumulation of Aβ and microglial release of inflammatory molecules, may occur.…”

Section: Cytokinesmentioning

confidence: 99%

“…One of the most potent stimuli is IFN-γ which is known to increase expression of cell surface markers [29,32,165] and to increase production of proinflammatory cytokines in vivo and in vitro [29,30,60,98,166]. IFN-γ is a T cell cytokine, primarily released from Th1 cells and natural killer cells, which plays a significant part in modulating growth, maturation, and differentiation of many immune cells [167].…”

Section: Ifn-γmentioning

confidence: 99%

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The Multifaceted Profile of Activated Microglia

2009

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Although relatively neglected previously, research efforts in the past decade or so have identified a pivotal role for glial cells in regulating neuronal function. Particular emphasis has been placed on increasing our understanding of the function of microglia because a change from the ramified "resting" state of these cells has been associated with the pathogenesis of several neurodegenerative diseases, notably Alzheimer's disease. However, it is not clear whether activation of microglia and the associated inflammatory changes play a part in triggering disease processes or whether cell activation is a response to the early changes associated with the disease. In either case, the possibility exists that modulation of microglial activation may be beneficial in some circumstances, underlying the need to pursue research in this area. The original morphological categorization of microglia by Del Rio Hortega into ameboid, ramified, and intermediate forms, must now be elaborated to encompass a functional description. The evidence which has been generated recently suggests that microglia are probably never in a "resting" state and that several intermediate transitional states, based on function and morphology, probably exist. A more complete understanding of these states and the triggers which lead to a change from one to another state, and the factors which modulate the molecular switch that determines the persistence of the "activated" state remain to be identified.

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Section: Cytokinesmentioning

confidence: 99%

Section: Ifn-γmentioning

confidence: 99%

The Multifaceted Profile of Activated Microglia

2009

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“…This may occur within the cells and at extracellular locations and greatly interferes with proper cell function. 20 In the present study we addressed the question whether protein aggregates with amyloid properties have the capacity to activate platelets. To avoid bias by other peptide domains, a number of unrelated proteins was modified and the appearance of amyloid properties was evaluated in platelet activation assays.…”

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confidence: 99%

Activation of Human Platelets by Misfolded Proteins

Herczenik

Bouma

Korporaal

et al. 2007

ATVB

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Objective-Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. Methods and Results-We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A 2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca 2ϩ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36 Ϫ/Ϫ mice), p38 MAPK (SB203580), COX-1 (indomethacin), and glycoprotein Ib␣ (Nk-protease, 6D1 antibody) induced Ϸ50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of ␣ IIb ␤ 3 -independent aggregation (agglutination). Conclusions-Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38 MAPK , thromboxane A 2 -mediated induction of aggregation; the other is through glycoprotein Ib␣-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid. Key Words: amyloid Ⅲ platelet activation Ⅲ sRAGE Ⅲ tissue plasminogen activator Ⅲ CD36 Ⅲ glycoprotein Ib␣ P roteins typically adopt a well-defined 3-dimensional structure. There is now an increasing amount of evidence that abnormalities in this process have far reaching consequences for human health. Certain mutations and posttranslational modifications such as glycation and oxidation interfere with proper folding, resulting in protein misfolding, aggregation, and ultimately polymerization into insoluble fibrils called amyloid. 1,2 The term amyloidosis defines a group of systemic and localized diseases associated with the deposition of amyloid in different tissues. Alzheimer disease is caused by abnormal folding of amyloid-␤ and formation of amyloid-rich plaques that obstruct neurons and microvessels of the brain. 3 One has argued that these plaques cause the hyperreactivity of platelets observed in these patients as illustrated by P-selectin positive platelets and increased levels of urinary thromboxane A 2 metabolite. 4,5 An environmental risk factor for Alzheimer disease is Herpes Simplex virus. It contains glycoprotein B, a protein fragment that assembles into fibrils that are ultrastructurally indistinguishable from amyloid-␤. 6 Protein misfolding is not restricted to Alzheimer disease but is a common feature in the pathology of atherosclerosis, diabetes mellitus, and systemic amyloidosis. 7-9 Atherosclerotic plaques contain ...

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“…32) The role of the inflammatory process has been underlined by the report that microglial cells derived from transgenic animals expressing the mutant form of the presenilin protein PS1 associated with the familial form of the disease are more susceptible to the actions of proinflammatory factors such as LPS, which also acts to potentiate the neurotoxic effects of the Aβ peptide. 33) In neuroinflammation, microglial scavenger function is impaired and reactivity against APP is enhanced as an initial step for neurodegeneration. 4) Hence, the inhibition of APP production by Res may result from its indirect action, and the exact mechanism needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Attenuates Neuroinflammation-mediated Cognitive Deficits in Rats

Gong

Jin

et al. 2010

JOURNAL OF HEALTH SCIENCE

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Neuroinflammatory responses are involved in Alzheimer's disease (AD) pathogenesis. In the present study, the protective effects of resveratrol, a polyphenolic compound, on cognitive deficits induced by lipopolysaccharide (LPS) were examined in rats, and the possible mechanisms were explored. The data showed that resveratrol administration by intraperitoneal injection (i.p.) may inhibit cognitive deficits induced by bilateral intracerebroventricular injection of 5 µg of LPS in rats. Subsequently, resveratrol afforded beneficial actions on the inhibition of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and amyloid-β protein precursor (APP) generation, as well as the inhibition of phospho-transcription factors of nuclear factor κB p65 (p-NF-κB p65) activation followed by the presence of LPS in rat hippocampus. The results of the present study indicate that resveratrol may attenuate LPSinduced direct neuroinflammation in rats, and its mechanisms are, at least partly, due to inhibition of the generation of TNF-α, COX-2, and APP, and the related phosphorylation of NF-κB. These findings suggest that resveratrol might be a potential agent for treatment of neuroinflammation-related diseases, such as AD.

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??-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon-gamma and "advanced glycation endproducts" in a mouse microglia cell line

Cited by 22 publications

References 0 publications

The Multifaceted Profile of Activated Microglia

The Multifaceted Profile of Activated Microglia

Activation of Human Platelets by Misfolded Proteins

Resveratrol Attenuates Neuroinflammation-mediated Cognitive Deficits in Rats

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