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At least 793 records · Page 44Linked to original sources
PubMed1999

Evidence for activation of microglia in patients with psychiatric illnesses.

Activation of microglia/macrophages is a key event in response to pathological changes in the CNS. HLA-DR is a valuable immunohistochemical marker that specifically reacts with activated microglia cells. In order to elucidate a potential role of microgliosis in severe psychiatric illnesses, post-mortem frontal cortex and hippocampus of patients with schizophrenia (n = 14) and affective disorder (n = 6) and control specimens (n = 13) were studied. Additionally Alzheimer's disease cases (n = 8) were included as a human model system with typical neurodegenerative alterations and microglia activation. All patient groups revealed subjects with abundant microglia immunostaining (schizophrenia, three patients; affective disorder, one patient; Alzheimer's disease, four patients) in both gray and white matter. This finding provides evidence for distinct neuropathological changes in brains of patients with schizophrenia and affective disorder. The activation of microglia cells, which represent a major part of the brain immune response, may help to unravel the pathophysiological processes in severe psychiatric illnesses.

Aged↗
PubMed2000

Expression of induced nitric oxide synthase in amoeboid microglia in postnatal rats following an exposure to hypoxia.

The present study showed the expression of induced nitric oxide synthase (iNOS) immunoreactivity in amoeboid microglia following an exposure to transient hypoxia in postnatal rats. iNOS immunoreactivity was expressed mainly in the amoeboid microglia in corpus callosum and subependymal regions of the ventricles within 3 h after hypoxia. The expression declined after 5 h, and became undetectable after 15 h and in longer surviving rats. The immunoreactivity of these cells with OX-42, which is a marker for microglia cells and detects complement type three receptors (CR3), was comparable in the rats exposed to hypoxia and the control rats. Immunoglobulin G (IgG) immunoreactivity was observed in the amoeboid microglia up to 3 h after hypoxia but it was undetectable in longer surviving rats and in the control rats. The iNOS expression in the amoeboid mircoglial cells may be related to the host defense and maintenance of structural integrity of the highly vulnerable periventricular white matter after hypoxia. The immunostaining of amoeboid microglial cells with IgG following hypoxia indicates leakage of plasma immunoglobulin from the blood vessels and its removal by the amoeboid microglial cells.

Animals↗
PubMed1997

Opiate signaling regulates microglia activities in the invertebrate nervous system.

1. Evidence supporting the presence in the invertebrate nervous system of a class of glial cells resembling vertebrate microglia was obtained in the freshwater snail Planorbarius corneus. These cells are easily identified by their immunopositivity to anti-pro-opiomelanocortin (POMC)-derived peptide antibodies. 2. Invertebrate microglia, as in vertebrates, exhibit macrophage-like activity in vivo and in cell cultures. These cells respond to the trauma of ganglionic excision and their organotypic culture by leaving their location around neurons and moving to the lesion site from which they migrate in the culture dish. 3. In vitro, these microglia undergo conformational changes and show phagocytic properties in the presence of bacteria or lipopolysaccharide. The activated cells also express tumor necrosis factor-alpha-like material and an increase in nitric oxide synthase, as shown by immunocytochemistry. 4. The inhibitory effect of morphine on the mobility and phagocytic activity of invertebrate microglia provide additional functional evidence for a possible role of opiate-like compounds in downregulating immunoregulatory processes, as also observed in the circulating immunocytes.

Animals↗
PubMed2000

Detection of substance P and its receptor in human fetal microglia.

Substance P, the most abundant neurokinin in the CNS, is a major modulator of the immune system. We have examined the gene expression of substance P and its receptor in human fetal brain microglia. Using reverse transcription-polymerase chain reaction and Southern blotting assay, the four isoforms of preprotachykinin-A gene transcripts (alpha, beta, gamma and delta) were detected in the microglia. The human fetal microglia produced significantly higher levels of endogenous substance P protein (640-850 pg/10(6) cells) than did human peripheral blood monocyte-derived macrophages (25-50 pg/10(6) cells), as determined by an enzyme immunoassay. Using immunohistochemical staining with an anti-substance P antibody, cell membrane substance P immunoreactivity was observed. In addition, we identified the presence of messenger RNA for neurokinin-1 receptor, a primary receptor for substance P in human fetal microglia.From these data, we propose that substance P and its receptor are biologically involved in regulating the functions of microglia, and potentially play an important role in host defense of the central nervous system.

Brain↗
PubMed2003

Phosphorylation of extracellular signal-regulated kinases 1/2 is predominantly enhanced in the microglia of the rat spinal cord following dorsal root transection.

The present study was initiated to investigate the role of extracellular signal-regulated kinases (ERK) 1/2 signaling pathway in the early response of spinal cord and associated dorsal root ganglion (DRG) to rhizotomy by using Western blotting and immunohistochemical techniques in a rat model of L3 and L4 dorsal root transection. The results showed that there were a considerable amount of total and phosphorylated ERK 1/2 protein in both spinal cord and DRG in normal animals killed under pentobarbital anesthesia. The total ERK 1/2 distributed in both glia and neurons, while phosphorylated ERK 1/2 dominantly existed in the latter in the gray matter of spinal cord, as demonstrated with double immunofluorescent staining. Twenty-four and forty-eight hours after axotomy, the phosphorylation level of ERK 1/2 in the operation side of dorsal spinal cord was much higher than that in the contralateral side, while the total ERK 1/2 level seemed unchanged. The increased expression of Fos protein was also seen in the dorsal spinal cord at lesion side twelve and twenty-four hours after axotomy. Double fluorescent staining proved that the phosphorylated ERK 1/2 positive cells in the ipsilateral dorsal spinal cord after axotomy predominantly were microglia and small portion was oligodendrocytes, whereas the Fos expression was mainly in neurons. In normal DRG, most neurons, especially the medium and small-sized ones, and the satellite cells contained total ERK 1/2-like immunoreactivity, whereas only a small portion of neurons and satellite cells contained phosphorylated ERK 1/2. After unilateral dorsal rhizotomy, there were no detectable changes for the phosphorylation of ERK 1/2 in either neurons or satellite cells in DRG.Collectively, the present results suggest that both ERK and Fos signal pathways involve the cellular activation in the spinal cord following dorsal rhizotomy, with ERK mainly in microglia and Fos in neurons. The increase of phosphorylation of ERK 1/2 in microglia of spinal cord after rhizotomy implicates that ERK signaling pathway involves intracellular activity of microglia responding to the experimental injury.

Animals↗
PubMed1997

Ion channels of human microglia in culture.

Macroscopic and microscopic currents have been recorded using human microglia isolated from fetal human brains (12-20 weeks gestation). Within a period of two days following plating of cells, inward K+ currents were small (mean amplitude of 0.3 nA at -100 mV) and outward K+ currents were not observed. For periods in excess of five days after adherence to substrate, an inactivating outward K+ current, sensitive to 4-aminopyridine, was expressed. A slowly rising current, blocked by tetraethylammonium, was also evident in a small population of human microglia. This current was activated with cell depolarization positive to +10 mV and had properties similar to those recently described for a proton current in mouse cells. In early adherent cells (days 1 or 2 after plating), treatment of microglia with interferon-gamma led to the expression of outward K+ current which was lacking in the absence of the treatment. In excised, inside-out patches, two high conductance channels were identified. A calcium-dependent K+ channel (unitary conductance of 106 pS with physiological levels of K+ across the patch) had an open probability of 0.5 with internal Ca2+ at 7 microM and the patch potential at 0 mV. In addition, an anion channel (unitary conductance of 280 pS) was transiently activated with depolarizing or hyperpolarizing steps applied from 0 mV. Characterization of the macroscopic and unitary properties of currents in microglia will have relevance to a description of putative cell functions in the human CNS. In particular, modification of cell electrophysiological properties by various activating stimuli may contribute to signalling processes in CNS pathology.

Anions↗
PubMed1999

Glutamate release from microglia via glutamate transporter is enhanced by amyloid-beta peptide.

In the present study, we found that amyloid-beta peptide enhanced glutamate release from primary cultured rat microglia via the Na+-dependent glutamate transporter, which was activated by extracellular K+. Glutamate transport current was measured by a conventional whole-cell patch recording mode under voltage-clamp conditions. With the pipette solution containing 10 mM glutamate and 100 mM Na+, an increase of the external K+ concentration from 0 to 10 mM evoked an outward current, resulting from co-extrusion of glutamate and Na+. The inward current, reflecting forward glutamate transport, was also activated by external glutamate. Both these reverse and forward glutamate transport currents were three-fold greater in microglia incubated with a relatively low concentration of amyloid-beta peptide (25-35) (5 microM) for four days. The glutamate-activated inward current was blocked by D,L-threo-beta-hydroxyaspartate in a dose-dependent manner (ranging from 0.001 to 1 mM), but not by a high concentration of kainate (1 mM). The glutamate concentration released from microglia upon high-K+ stimulation was also significantly increased (up to 170 microM) after treatment with amyloid-beta peptide (25-35). These results suggest that, at the pathological sites where extracellular K+ concentration may increase, the activation of microglia by amyloid-beta peptide causes an increase in extracellular glutamate concentration via reverse glutamate transporter, and therefore this mechanism may contribute to the pathogenesis of neuronal dysfunction and death in Alzheimer's disease.

ATP-Binding Cassette Transporters↗
PubMed2003

Cell cycle protein expression in proliferating microglia and astrocytes following transient global cerebral ischemia in the rat.

Cerebral ischemia induces microglial and astroglial activation, which may play a crucial role in the development of ischemic neuronal damage. In this study, we examined the role of cell cycle proteins in glial proliferation in the hippocampus following 10min of global cerebral ischemia in the rat. Proliferating cells were identified with immunostaining for proliferating cell nuclear antigen (PCNA), and glial cells were visualized with immunostaining for microglial response factor-1 (microglia/macrophages) and glial fibrillary acidic protein (astrocytes). Expression of cyclin D1 and cyclin-dependent kinase-4 was also examined with double label immunohistochemistry. Proliferating cells in the CA1 region after ischemia consisted of microglia and much fewer astrocytes. Microglial activation and proliferation (7.6-fold increase in number after 7 days) were preceded by an increase in PCNA-positive microglia; 83% of microglia were PCNA-positive after 2 days. Astrocytes increased by 1.8-fold after 7 days, and only 6% of astrocytes became PCNA-positive by day 7. Cyclin D1 and cyclin-dependent kinase-4 immunoreactivity appeared in these glial cells in parallel with the expression of PCNA. The findings suggest that the accumulation of brain macrophages elicited by transient cerebral ischemia is caused predominantly by activation and proliferation of resident microglia through the upregulation of cell cycle proteins.

Analysis of Variance↗
PubMed1996

Temporal characterization of microglia, IL-1 beta-like immunoreactivity and astrocytes in the dentate gyrus of hippocampal organotypic slice cultures.

These studies demonstrate that murine hippocampal slice cultures possess neural-immune elements that show responses parallel to comparable in vivo models of neural-immune activation. Using immunocytochemical techniques, this study characterized the phenotypes of specific glial elements and the expression of the cytokine, interleukin-1 (IL-1 beta), in the hippocampal dentate gyrus over a period of 10 days in vitro (DIV). Preparation of organotypic slice cultures of neonatal mouse hippocampus produced cellular damage including axotomy of afferent fibers within the molecular layer of the dentate gyrus. This form of lesion-induced injury caused activation of neural-immune elements in the slice cultures. Staining with the microglial specific biotinylated Griffonia simplicifolia B4-isolectin revealed reactive microglia were most prevalent at 2 DIV and decreased in number from 4 to 10 DIV, whereas the initial population of resting microglia at 2 DIV increased approximately four-fold from 4 to 10 DIV. The presence of a round IL-1 beta-like immunophenotype closely paralleled the temporal and spatial distribution of the reactive form of microglia observed in the dentate gyrus. In addition, between 4 and 10 DIV, some IL-1 beta-like immunoreactive cells exhibited a stellate-like morphology with numerous branching processes, similar to resting microglia. At 2 DIV astrocytes showed minimal labeling with antibodies directed against glial fibrillary acidic protein (GFAP), while from 4 to 10 DIV, a dramatic hypertrophic astrocytic response occurred, resulting in a gliotic scar forming over the entire dentate gyrus. We conclude that neural-immune activation in the hippocampal organotypic slice culture preparation closely parallels similar responses observed in vivo and thus slice cultures represent an excellent model for further studies of neural-immune interactions resulting from lesion-induced injury in the central nervous system.

Animals↗
PubMed1998

Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus.

BACKGROUND: Injury to the brain induces dramatic local changes in gene expression, cellular morphology and behavior. Activation of microglial cells occurs as an early event after central nervous system (CNS) injury, but it has not been determined whether such activation plays a causal role in neuronal death. We have investigated this question using an excitotoxin-mediated brain injury model system, in conjunction with an endogenous peptide factor (macrophage/microglial inhibiting factor, MIF) that ablates microglial contribution to the cascade. RESULTS: Using MIF, we inhibited the microglial activation that normally follows excitotoxic injury. In cell culture studies, we found that such inhibition blocked the rapid release of microglia-derived tissue plasminogen activator (tPA), an extracellular serine protease made by both neurons and microglia, which we had previously identified as mediating a critical step in excitotoxin-induced neuronal death. Finally, infusion of MIF into the mouse brain prior to excitotoxic insult resulted in the protection of neurons from cell death. CONCLUSIONS: Our results demonstrate that microglia undertake a neurotoxic role when excitotoxic injury occurs in the CNS. They also suggest that the tPA released from microglia has a critical role in triggering neurodegeneration.

Animals↗
PubMed2003

Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages.

Microglia and macrophages express the alpha(M)/beta(2) integrin complement-receptor-3 (CR3/MAC-1; CD11b/CD18) and scavenger-receptor-AI/II (SRAI/II). Both can mediate myelin phagocytosis. We document that CR3/MAC-1 mediated myelin phagocytosis in microglia is modulated by complement and anti-CR3/MAC-1 mAbs. Complement augmented phagocytosis twofold. Anti-alpha(M) mAbs M1/70 and 5C6 inhibited and anti-beta(2) mAb M18/2 augmented myelin phagocytosis in the presence and absence of active complement. Active complement modulated phagocytosis inhibition by M1/70 and 5C6 and phagocytosis augmentation by M18/2. CR3/MAC-1 mediated myelin phagocytosis may thus be, at least partially, independent of but modulated by complement. Anti-beta(2) mAb Game-46 did not affect phagocytosis. However, combining M18/2 with Game-46 resulted in phagocytosis augmentation that was larger in magnitude than that induced by M18/2 alone. Thus, phagocytosis augmentation induced by one anti-beta(2) mAb was potentiated by another anti-beta(2) mAb. Combining M1/70 or 5C6 with M18/2 inhibited M18/2-induced augmentation. Overall, mAbs-induced phagocytosis modulation ranged three- to sevenfold from inhibition to augmentation. Anti-CR3/MAC-1 mAbs may reveal a mechanism by which native extracellular molecules bind to and modulate CR3/MAC-1 mediated myelin phagocytosis in microglia and macrophages. We further document SRAI/II mediated myelin phagocytosis in microglia and CR3/MAC-1 contributing to myelin phagocytosis two- to threefold more than SRAI/II when the two receptors function together.

Animals↗
PubMed2003

Defense mechanisms of IFN-gamma and LPS-primed murine microglia against Acanthamoeba castellanii infection.

In the central nervous system (CNS), cytokine-primed microglia play a central role in host's defense against Acanthamoeba castellanii infection. In this study, the effect of recombinant interferon (rIFN)-gamma and Salmonella enterica serovar enteritidis lipopolysaccharide (LPS), both inflammatory stimuli, on A. castellanii infection in murine microglia was examined. Priming of microglia with rIFN-gamma and LPS synergistically triggered, in a dose-dependent manner, amebastatic activity in these cells. More than 52%, 88% or 95% of this function was then abrogated by anti-IL-1beta (but not anti-IL-1alpha), IL-6 or TNF-alpha neutralizing antibodies, suggesting that these endogenously produced cytokines may participate in the antimicrobial capacity. Consistent with these findings, the priming of microglia with rIFN-gamma and LPS elicited the release of proinflammatory interleukin (IL)-1alpha, IL-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. Since L-canavanine affected amebastatic activity only during the priming process but not during the infection process, NO-dependent pathway appears to be not the sole antiparasitic mechanism involved in this function. These data suggest that rIFN-gamma and LPS, likely through a proinflammatory network, up-regulate the release of IL-beta, IL-6 and TNF-alpha, which could trigger antimicrobial activity against A. castellanii infection in the brain.

Acanthamoeba↗
PubMedDate not supplied

Microglia in the nerve fiber layer of the cat retina: detection of postnatal changes by a new monoclonal antibody.

This paper describes changes in the appearance and distribution of microglia in postnatal cat retina as demonstrated by a new antibody, H386F. This fractionated IgM antibody was created via an intrasplenic immunization of a single BALB/C mouse with about 2-3 x 10(5) large, whole cells isolated from 46 minced cat retinae. To confirm that the labeled cells are microglia, the staining properties of H386F were compared with those of four commercially available antibodies, OX-33, OX-41, OX-42, and ED-1, that have been used by others to distinguish between microglia and other cells in rat brain. These experiments show that H386F is the only antibody of the five to label only microglia in both the cat retina and hippocampus.

Animals↗
PubMed2000

Morphological changes and expression of protein kinase CK2 beta subunit in the microglia after hypoglossal nerve transection.

Following hypoglossal nerve transection, the microglia of the rat hypoglossal nucleus expressed protein kinase CK2 beta subunit immunoreactivity. CK2 beta immunostaining occurred on the operated side from postoperative day 3; on day 5 we observed strong immunoreactivity and the immunopositive microglial cell processes surrounded the injured neurones. Thereafter, the immunoreactivity decreased gradually and on day 10 the immunopositive cells surrounded only a few injured neurones. Electron microscopic observations on the hypoglossal nucleus revealed microglia-neuronal contact within 3 hours of nerve injury, and by day 3 all the injured neurones were in contact with microglial cells. These observations indicated that microglia-neuronal contact occurred earlier than the CK2 beta subunit immunoreactivity. CK2 may not be implicated during the initial migration of the microglia to the injured neurones; however, it may enhance the growth and elongation of the microglial cell processes around the injured neurones.

Animals↗
PubMed1997

Population control of microglia: does apoptosis play a role?

Brain lesions, even of the most subtle type, are accompanied by the activation of microglia, the main immune cells of the brain. Microglial cells dramatically increase in number through proliferation and adhere to the injured neurons, where they displace the synaptic input. After proliferation, microglia gradually migrate into the nearby parenchyma and appear to decrease in number. Here we examined the possible involvement of apoptosis in the regulation of the microglial cell number using Terminal transferase mediated d-UTP Nick End-Labelling (TUNEL). In vitro, cell death is a common phenomenon in microglial cell cultures, and is enhanced by the withdrawal of the mitogen, granulocyte-macrophage colony stimulating factor. In vivo, application of the TUNEL-reaction revealed TUNEL-positive microglia beginning at day 4, with a peak 7 days after transection of the facial nerve. Surprisingly, TUNEL-labelling in vivo was localized on the outer side of the nuclear membrane and in the microglial cytoplasm, with very little staining within the nucleus itself. These TUNEL-labelled cells also lacked other classic morphological signs of apoptosis, like membrane blebbing, chromatin condensation and apoptotic bodies. These data suggest that the regulation of post-mitotic microglia is not mediated by the classic pathway of apoptosis.

Animals↗
PubMed1997

PK ('peripheral benzodiazepine')--binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia.

The isoquinoline PK11195 has been suggested as a marker of glial pathology in the lesioned brain. The aim of the present study is to clarify the precise cellular location of its binding site in the central nervous system. Here, we report that in the facial nucleus after facial nerve axotomy-a lesion causing a retrograde neuronal reaction without nerve cell death while keeping the blood-brain barrier intact--activated microglia are the predominant source of lesion-induced increases of PK11195 binding. Likewise, increased PK11195 binding is seen in the gracile nucleus after anterograde neuronal injury following sciatic nerve transection. The peak of PK11195 binding, using the single isomer R-PK11195, was observed 4 days after the peripheral nerve lesion, consistent with the well-known time course of microglial activation. Photoemulsion microautoradiography confirmed the restriction of PK11195 binding to activated microglia. The increase of PK11195 binding in the facial nucleus seen after selective cell death of facial motoneurons by retrograde suicide transport of toxic ricin, a lesion that is accompanied by the rapid transformation of microglia into phagocytes, was no higher than that seen following axotomy. This suggests that the full transformation of microglia into parenchymal phagocytes is not necessary to reach maximal levels of PK11195 binding. PK11195, therefore, is a well-suited marker to detect microglial activation in areas of subtle brain pathology, where neither a disturbance of the blood-brain barrier function nor the presence of macrophages and inflammatory cells indicate an on-going disease process.

Animals↗
PubMed1996

Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils.

A pathological hallmark of Alzheimer's disease is the senile plaque, containing beta-amyloid fibrils, microglia and astrocytes. Beta-amyloid fibrils exert a cytotoxic effect on neurons, and stimulate microglia to produce neurotoxins, such as reactive oxygen species. Mononuclear phagocytes, including microglia, express scavenger receptors that mediate endocytosis of oxidized low-density lipoproteins, and adhesion to glucose-modified extra-cellular matrix proteins. Here we report that class A scavenger receptors mediate adhesion of rodent microglia and human monocytes to beta-amyloid fibril-coated surfaces leading to secretion of reactive oxygen species and cell immobilization. Thus, class A scavenger receptors are potential therapeutic targets in Alzheimer's disease.

Alzheimer Disease↗
PubMed2006

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease.

Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1beta, TNF-alpha, IL-6), NO, PGE(2), and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

AIDS Dementia Complex↗