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ABSTRACT: Microglia are the immune cells in the central nervous system. After injury microglia release bioactive molecules, including cytokines and ATP, which modify the functional state of hemichannels (HCs) and gap junction channels (GJCs), affecting the intercellular communication via extracellular and intracellular compartments, respectively. Here, we studied the role of extracellular ATP and several cytokines as modulators of the functional state of microglial HCs and GJCs using dye uptake and dye coupling techniques, respectively. In microglia and the microglia cell line EOC20, ATP advanced the TNF-α/IFN-γ-induced dye coupling, probably through the induction of IL-1β release. Moreover, TNF-α/IFN-γ, but not TNF-α plus ATP, increased dye uptake in EOC20 cells. Blockade of Cx43 and Panx1 HCs prevented dye coupling induced by TNF-α/IFN-γ, but not TNF-α plus ATP. In addition, IL-6 prevented the induction of dye coupling and HC activity induced by TNF-α/IFN-γ in EOC20 cells. Our data support the notion that extracellular ATP affects the cellular communication between microglia through autocrine and paracrine mechanisms, which might affect the timing of immune response under neuroinflammatory conditions.
Mediators of Inflammation 01/2013; 2013:216402. · 3.26 Impact Factor
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ABSTRACT: Amyloid-beta plaques and neurodegeneration are hallmarks of Alzheimer's disease, where glial cells are responsible for sustained neuroinflammation. Here we show that hippocampal-microglia co-cultures exposed to proinflammatory mediators, amyloid-beta- and amyloid-beta protein precursor construct-conjugated beads increased their production of nitrites. In contrast, inflammation was unable to significantly induce cell death by itself, whereas inflammation plus amyloid-beta or amyloid-beta protein precursor induced a significant increment of cell death and a 6-fold increase of production of Interleukin 1beta. Those effects were not observed in the absence of microglia or when hippocampal cells were co-cultured with microglia for one day. In contrast, a 2-fold increase of transforming growth factor beta1 was observed in hippocampal cultures exposed to inflammatory stimuli for 4 days, whereas induction of transforming growth factor beta1 by inflammation plus amyloid-beta and amyloid-beta protein precursor was nearly abolished by microglia. Our results indicate that neurotoxicity induced by amyloid-beta or amyloid-beta protein precursor was a slow process depending on activated microglia and additional stimuli. The observed cytotoxicity could be consequence of a vicious cycle in which elevated concentrations of Interleukin 1beta and radical species along with decreased secretion of neuroprotective cytokines such as transforming growth factor beta1 support persistent activation of glial cells and cell damage.
Journal of Alzheimer's disease: JAD 10/2008; 15(1):45-59. · 3.74 Impact Factor
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ABSTRACT: Aberrant handling of Amyloid Precursor Protein (APP) and beta-amyloid (Abeta), glial activation and inflammation are key events in Alzheimer's disease. We set out to determine the role of inflammation on microglial reactivity against APP. We studied microglia-mediated neurotoxicity, uptake and degradation of a biotinylated APP construct (biotin-APP-C-244). APP, in contrast to Abeta, only induced mild activation of glial cells. However, under pro-inflammatory conditions, APP induced microglial-mediated cytotoxicity. Biotin-APP-C-244 or lipopolysaccharide and interferon-gamma (LPS+IFNgamma), administered separately, did not change reduction metabolism of microglia. However, biotin-APP-C-244+(LPS+IFNgamma) increased microglial reactivity and decreased reduction metabolism by 75% (P<0.001). Biotin-APP-C-244 was readily taken up by microglial cells; 80% was phagocytosed at 2 h. In the presence of LPS+IFNgamma, phagocytosis of biotin-APP-C-244 was reduced at 2 h; and cell damage was evident after 4 h. Our results support our hypothesis that, in neuroinflammation, microglial scavenger function is impaired and reactivity against APP enhanced as an initial step for neurodegeneration.
Neurobiology of Disease 05/2007; 26(1):153-64. · 5.40 Impact Factor
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ABSTRACT: Research on Alzheimer's disease (AD) focuses mainly on neuronal death and synaptic impairment induced by beta-Amyloid peptide (Abeta), events at least partially mediated by astrocyte and microglia activation. However, substantial white matter damage and its consequences on brain function warrant the study of oligodendrocytes participation in the pathogenesis and progression of AD. Here, we analyze reports on oligodendrocytes' compromise in AD and discuss some experimental data indicative of Abeta toxicity in culture. We observed that 1 microM of fibrilogenic Abeta peptide damages oligodendrocytes in vitro: while pro-inflammatory molecules (1 microg/ ml LPS + 1 ng/ml IFNgamma) or the presence of astrocytes reduced the Abeta-induced damage. This agrees with our previous results showing an astrocyte-mediated protective effect over Abeta-induced damage on hippocampal cells and modulation of the activation of microglial cells in culture. Oligodendrocytes protection by astrocytes could be, either by reduction of Abeta fibrilogenesis/deposition or prevention of oxidative damage. Likewise, the decrease of Abeta-induced damage by proinflammatory molecules could reflect the production of trophic factors by activated oligodendrocytes and/or a metabolic activation as observed during myelination. Considering the association of inflammation with neurodegenerative diseases. oligodendrocytes impairment in AD patients could potentiate cell damage under pathological conditions.
Biological research 02/2005; 38(4):381-7. · 1.03 Impact Factor
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ABSTRACT: Maternal omega-3 fatty acid supplementation has been suggested to provide docosahexaenoic acid (DHA) for the normal brain development during gestation. DHA can be given as such (preformed) or through the omega-3 precursor alpha-linolenic acid (LNA) which is transformed into DHA by elongation and desaturation reactions. Western diet provides low amounts of LNA and DHA; therefore, supplementation with these omega-3 fatty acids has been suggested for pregnant women. However, the bioequivalence of LNA ingestion to DHA supplementation has not been established.
Recently weaning female Wistar rats were fed a diet containing a small amount of LNA and no DHA. The animals were daily supplemented 40 days before mating, during pregnancy, and until delivery with 60 mg/kg of LNA or 6 mg/kg of DHA dissolved in coconut oil. Fatty acids were given as ethyl ester derivatives. Controls received coconut oil. The fatty acid composition of blood plasma, erythrocytes, liver, visceral adipose tissue, and brain segments (frontal cortex, hippocampus, and cerebellum) was analyzed. Brain segments obtained from 16- and 19-day-old fetuses and from 2- and 21-day-old rats were also analyzed for fatty acid composition.
Supplementation with LNA and DHA induced a similar accretion of DHA in plasma, erythrocytes, liver, and brain segments of the mothers. The adipose tissue showed a higher DHA accretion after DHA-supplementation. The DHA accretion in frontal cortex, hippocampus, and cerebellum obtained from the fetuses and the newborn rats was similar when the mothers were supplemented with LNA and DHA. Our results show that under our experimental conditions a similar accretion of DHA in the different tissues of the mothers and in the brain segments of fetuses and newborn rats is obtained after LNA and DHA supplementation.
LNA and DHA, at the amounts given in this study, show a similar bioequivalence for DHA accretion in different tissues of the mother and in brain segments of fetuses and newborn rats.
Annals of Nutrition and Metabolism 02/2004; 48(1):28-35. · 2.26 Impact Factor
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ABSTRACT: Acetylcholinesterase (AChE) activities in CNS physiopathology are increasingly diverse and range from neuritogenesis, through synaptogenesis, to enhancement of amyloid fiber assembly. In Alzheimer's disease, senile plaques and neurodegeneration specially affect regions enriched for cholinergic synapses. In this study we show an effect of AChE that could contribute to the increased deposition of Abeta in certain regions. Affinity-purified AChE induced the expression of amyloid-beta-precursor protein (beta-APP) in glial cells in a concentration-dependent manner up to 5 nM. In glia, AChE also increased inducible nitric oxide synthase (iNOS) assessed by immunocytochemistry and decreased reductive metabolism as evidence of cell activation. AChE could increase the expression of beta-APP in astrocytes and microglia as result of the activation of glial cells. As a whole, we found that AChE has additional effects that could result in an increased synthesis of Abeta, both by increasing beta-APP expression of astrocytes and by further activating glial cells.
Neurobiology of Disease 01/2004; 14(3):447-57. · 5.40 Impact Factor
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ABSTRACT: The brain of Alzheimer's disease patients shows abundant dystrophic neurites in close proximity to fibrillar beta-amyloid (A beta) plaques, and activated glial cells. We evaluated the influence of pro-inflammatory molecules (LPS + IFN-gamma) on A beta(1-42) neurotoxicity. 2 microM A beta(1-42) induced apoptosis of hippocampal cells and LPS + IFN-gamma reduced the apoptosis induced by A beta. However, LPS + IFN-gamma prevented apoptosis only in hippocampal cultures containing astrocytes. Also, LPS + IFN-gamma induced the secretion of TGF beta, a cytokine having neuroprotective effects, only in hippocampal cultures that contained astrocytes. Astrocytes had a regulatory effect over microglial and neuronal responses to A beta. The results suggest that LPS + IFN-gamma, traditionally considered as pro-apoptotic, reduced apoptosis induced by A beta through the activation of neuroprotective mechanisms mediated by astrocytes. We propose that astrocytes are pivotal in the modulation of inflammation of the CNS. The impairment of the regulatory functions performed by activated astrocytes could represent an important pathogenic mechanism for neurodegenerative diseases.
Neurobiology of Disease 19(1-2):243-54. · 5.40 Impact Factor
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ABSTRACT: Acetylcholinesterase (AChE) activities in CNS physiopathology are increasingly diverse and range from neuritogenesis, through synaptogenesis, to enhancement of amyloid fiber assembly. In Alzheimer's disease, senile plaques and neurodegeneration specially affect regions enriched for cholinergic synapses. In this study we show an effect of AChE that could contribute to the increased deposition of Aβ in certain regions. Affinity-purified AChE induced the expression of amyloid-β-precursor protein (β-APP) in glial cells in a concentration-dependent manner up to 5 nM. In glia, AChE also increased inducible nitric oxide synthase (iNOS) assessed by immunocytochemistry and decreased reductive metabolism as evidence of cell activation. AChE could increase the expression of β-APP in astrocytes and microglia as result of the activation of glial cells. As a whole, we found that AChE has additional effects that could result in an increased synthesis of Aβ, both by increasing β-APP expression of astrocytes and by further activating glial cells.
Neurobiology of Disease.
