MicroGlial reactivity to β-amyloid is modulated by astrocytes and proinflammatory factors
Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile. Brain Research
(Impact Factor: 2.84).
11/2004; 1025(1-2):186-93. DOI: 10.1016/j.brainres.2004.07.084
The brains of Alzheimer's disease (AD) patients present activated glial cells, amyloid plaques and dystrophic neurites. The core of amyloid plaques is composed of aggregated amyloid peptide (Abeta), a peptide known to activate glial cells and to have neurotoxic effects. We evaluated the capability of glial cells to mediate Abeta(1-42) cytotoxicity in hippocampal cultures. Conditioned media obtained from microglial cultures exposed to Abeta induced apoptosis of hippocampal cells. This pro-apoptotic effect was not observed in hippocampal cultures exposed to conditioned media obtained from mixed glial (astrocytes and microglia) cultures that had been exposed to Abeta. Microglia exposed to Abeta responded with reactive morphological changes, induction of iNOS, elevated nitric oxide production and decreased reductive metabolism. All these responses were attenuated by the presence of astrocytes. This astrocyte modulation was however, not observed when glial cells were exposed to proinflammatory factors (LPS+Interferon-gamma) alone or in combination with Abeta. Our results suggest that astrocytes and proinflammatory molecules are determining factors in the response of microglia to Abeta.
Available from: PubMed Central
- "Conditioned media from microglia exposed to Aβ induce apoptosis in hippocampal cells, but this effect is not observed when the media is obtained from mixed glial cultures exposed to Aβ. Many of the inflammatory activation changes of microglial cell induced by Aβ are attenuated in the presence of astrocytes . Moreover, astrocytes activation mediated by LPS and IFN-γ induce the secretion of TGF-β, a neuroprotective cytokine, which was capable of reducing apoptosis of hippocampal cells induced by Aβ , suggesting that astrocytes have a pivotal role in the modulation of AD inflammation. "
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ABSTRACT: It is widely accepted that cells serving immune functions in the brain, namely, microglia and astrocytes, are important mediators of pathological phenomena observed in Alzheimer's disease. However, it is unknown how these cells initiate the response that results in cognitive impairment and neuronal degeneration. Here, we review the participation of the immune response mediated by glial cells in Alzheimer's disease and the role played by scavenger receptors in the development of this pathology, focusing on the relevance of class A scavenger receptor (SR-A) for A β clearance and inflammatory activation of glial cell, and as a potential target for Alzheimer's disease therapy.
Available from: Stephan Röskam
- "Von Bernhardi et al. observed that microglia exposed to Aβ respond with reactive morphological changes, induction of inducible nitric oxide synthase (iNOS), elevated nitric oxide production and decreased reductive metabolism. All these responses were attenuated by the presence of astrocytes . Astrocytes are also involved in Aβ degradation and removal and play an important role in maintaining physiological homeostasis in the brain. "
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Naturally occurring autoantibodies against amyloid-β (nAbs-Aβ) have been shown to exert beneficial effects on transgenic Alzheimer’s disease (AD) animals in vivo and on primary neurons in vitro. Not much is known about their effect on microglial cells. Our aim was to investigate the effect of nAbs-Aβ on amyloid-β (Aβ)-treated microglial cells in vitro with respect to cell viability, stress pathways, cytokine production and phagocytotic abilities and whether these effects can be conveyed to neurons.
Primary microglial cells isolated from Swiss Webster mouse mesencephalons on embryonic day 13.5 were pretreated with nAbs-Aβ and then treated with Aβ oligomers. After 3 hours, phagocytosis as well as western blot analysis were evaluated to measure the amount of phagocytized Aβ. Cell viability was analyzed using an MTT assay 24 hours after treatment. Pro-inflammatory cytokines in the supernatants were analyzed with ELISAs and then we treated primary neuronal cells with these conditioned microglia supernatants. Twenty-four hours later we did a MTT assay of the treated neurons. We further investigated the effect of a single nAbs-Aβ administration on Tg2576 mice in vivo.
Upon co-administration of Aβ and nAbs-Aβ no change in microglia viability was observed. However, there was an increase in phosphorylated p38 protein level, an increase in the pro-inflammatory cytokines TNF-α and IL-6 and an increase in Aβ uptake by microglial cells. Treatment of primary neurons with conditioned microglia medium led to a 10% improvement in cell viability when nAbs-Aβ were co-administered compared to Aβ-treated cells alone. We were unable to detect changes in cytokine production in brain lysates of Tg2576 mice.
We provide evidence on the mechanism of action of nAbs-Aβ on microglia in vitro. Interestingly, our in vivo data indicate that nAbs-Aβ administration should be considered as a therapeutic strategy in AD, since there is no inflammatory reaction.
Available from: Juan Tichauer
- "We obtained mixed glial cultures from cerebral cortex of 1–2-day-old Sprague-Dawley rats as previously described (Giulian and Baker 1986; von Bernhardi and Eugenín, 2004). We rinsed cortices with HBSS, removed meninges, minced the tissue, and incubated it with HBSS containing 0.25% trypsin-EDTA at 378C for 10 min. "
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ABSTRACT: Inflammatory cytokines and β amyloid (Aβ) induce activation of glial cells, leading to both protective and deleterious changes that are relevant for the pathogenesis of Alzheimer disease (AD). We have shown that astrocytes downregulate microglial cell cytotoxic activation through secretion of transforming growth factor-β (TGFβ1), and there is evidence that TGFβ1 modifies Aβ removal through the modulation of microglia. However, inflammatory activation of microglia is increased and Aβ clearance is reduced in AD patients, regardless of the fact that TGFβ1 is increased in their nervous system. We propose that changes in TGFβ Smad3 signal transduction could modify the regulation mediated by TGFβ1. Here we evaluated the participation of the TGFβ Smad3 pathway in regulation of the expression pattern of scavenger receptors (SR) and activation of microglia through nitric oxide (NO·) secretion and phagocytosis of Aβ. We found that TGFβ1 increased SR-A by 2.4-fold and decreased SR-BI expression by 79% at 48 hr, whereas it did not change SR-MARCO or CD36 expression. In addition, we observed a 51% increase of Aβ uptake and an 83% decrease of NO· production induced by lipopolysaccharide in microglial cell cultures. Increased expression of SR-A, phagocytosis, and downregulation of NO· by TGFβ1 were prevented by the inhibition of the TGFβ Smad3 pathway. Our results indicate that the modulation of microglial cell activation by TGFβ1, leading to increased clearance of Aβ and reduced cytotoxicity, is at least partially mediated by the Smad pathway.
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