Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors.
ABSTRACT 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.
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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.Journal of Neuroscience Research 10/2012; 90(10):1970-80. DOI:10.1002/jnr.23082 · 2.73 Impact Factor
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ABSTRACT: Among multiple structural and functional brain changes, aging is accompanied by an increase of inflammatory signaling in the nervous system as well as a dysfunction of the immune system elsewhere. Although the long-held view that aging involves neurocognitive impairment is now dismissed, aging is a major risk factor for neurodegenerative diseases such as Alzheimer;s disease, Parkinson;s disease and Huntington's disease, among others. There are many age-related changes affecting the brain, contributing both to certain declining in function and increased frailty, which could singly and collectively affect neuronal viability and vulnerability. Among those changes, both inflammatory responses in aged brains and the altered regulation of toll like receptors, which appears to be relevant for understanding susceptibility to neurodegenerative processes, are linked to pathogenic mechanisms of several diseases. Here, we review how aging and pro-inflammatory environment could modulate microglial phenotype and its reactivity and contribute to the genesis of neurodegenerative processes. Data support our idea that age-related microglial cell changes, by inducing cytotoxicity in contrast to neuroprotection, could contribute to the onset of neurodegenerative changes. This view can have important implications for the development of new therapeutic approaches.Journal of Neurochemistry 12/2009; 112(5):1099-114. DOI:10.1111/j.1471-4159.2009.06537.x · 4.24 Impact Factor
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ABSTRACT: A glia-mediated inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). In vitro, besides a direct neurotoxic effect on neurons, Abeta activates glia to produce an array of inflammatory factors including tumor necrosis factor-alpha (TNF-alpha), reactive oxygen species (ROS), nitric oxide (NO) and inducible nitric oxide synthase (iNOS), which accelerate the progression of AD. Catalpol, an iridoid glycoside, isolated from the root of Rehmannia glutinosa, protects neuronal cells from damage caused by a variety of toxic stimulus. In the present study, the effect of catalpol against Abeta(1-42)-induced neurotoxicity in primary cortical neuron-glia cultures as well as its mechanism acting on cells was further investigated. Pretreatment with catalpol at the dosage of 500 microM for 30 min prior to 5 microM Abeta(1-42) not only attenuated the Abeta(1-42)-triggered neurotoxicity to neurons but also inhibited the glial activation to some extent, which was examined by inspecting the morphological changes and measuring the release of the above mentioned inflammatory factors. Therefore, the results demonstrated that catalpol might be a promising anti-inflammatory agent in the therapy or prevention of neurodegenerative diseases associated with inflammation.Brain Research 02/2008; 1188:139-47. DOI:10.1016/j.brainres.2007.07.105 · 2.83 Impact Factor