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PubMed1993

Dipeptidyl peptidase II in astrocytes of the rat brain. Meningeal cells increase enzymic activity in cultivated astrocytes.

Astrocytes grown in media conditioned by meningeal cells (MCM) develop cellular processes and markedly increased protein per cell. One protein component affected is the dipeptidyl peptidase II (DPP II). The increase of DPP II activity is dose- and time-dependent and can also be elicited by the second messenger cAMP. More mature astrocytes express higher levels of DPP II than immature proliferating astrocytes. The rate of proliferation of astrocytes is markedly enhanced by enriched MCM. These observations lead to the assumption that DPP II has a function within the catabolic processes of cellular differentiation. To assess whether the in vitro results may reflect in vivo conditions, we investigated the postnatal development of DPP II in the rat brain. Differentiating astrocytes in vivo are especially found early postnatally and, indeed, during this period high specific activities are found in brain. Depending on the region investigated DPP II activities decrease within the first ten days to one fourth of their P2 level and finally reach at about similar levels in all brain regions. Exceptions are the hypothalamus, where the activity is generally 1.5- to 3-fold higher than elsewhere in brain, and pons and mesencephalon, where the perinatal activity peak is lacking. The bulk activity of DPP II in immature rat brains is attributed to differentiating astrocytes loosing it in later postnatal stages due to a neuronal influence.

Animals↗

PubMed1995

Reactions of astrocytes and microglial cells around hematogenous metastases of the human brain. Expression of endothelin-like immunoreactivity in reactive astrocytes and activation of microglial cells.

An immunohistochemical study was made on the peritumoral gliosis which is produced around hematogenous metastases of the human brain. The material was derived from 73 autopsy cases with different primary malignancies and six control cases without evidence of brain disease. Reactive astrocytes of hypertrophic and gemistocytic types were present around and within all the metastases. Eighty-five percent of the cases with metastases showed expression of endothelin-like immunoreactivity in the peritumoral astrocytes. Such immunoreactive astrocytes were not present in the normal controls but have previously been found in reactive astrocytes around infarcts, lacunas, inflammatory and degenerative brain diseases. The endothelin-like immunoreactivity probably reflects an increased intracellular content of endothelin. If this peptide is released from the reactive astrocytes it may act as a mitogen and influence microcirculation by inducing vasoconstriction. Activation of microglial cells, detected by ferritin immunohistochemistry, was another frequent and widespread glial cell alteration around the metastases. In conclusion, the reactive gliosis, which is formed around metastases involves activated astrocytes as well as activated microglial cells. Both cell types can release numerous biologically active compounds which may influence the structure and function of the brain tissue around the metastases.

Adolescent↗

PubMed1993

Diversity among reactive astrocytes: proximal reactive astrocytes in lacerated spinal cord preferentially react with monoclonal antibody J1-31.

An Astrocyte-specific antigen recognized by monoclonal antibody J1-31 is a more intense marker for proximal reactive astrocytes in lacerated rat spinal cord than is glial fibrillary acidic protein (GFAP). Thus, MAb J1-31 recognizes reactive astrocytes in the immediate vicinity of the lesion, whereas reactive astrocytes that are located at a distance from the lesion are not detected by immunofluorescent staining. These findings are relevant to the biochemical heterogeneity manifested respectively by reactive astrocytes located proximal and distal to a laceration-type injury of the spinal cord, and those that develop following axotomy with retrograde degeneration. Reactive astrocytes in the axotomy model are not stained with MAb J1-31, but are positive for GFAP.

Animals↗

PubMedDate not supplied

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta.

The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have distinct properties from apoE derived from other sources. To develop an efficient system to produce astrocyte-derived apoE in large quantities, we produced and characterized immortalized cell lines from primary astrocyte cultures derived from human APOE knock-in mice. APOE2, APOE3, and APOE4 expressing cell lines were established that secrete apoE in HDL-like particles at similar levels, cholesterol composition, and size as those produced by primary astrocytes. In physiological buffers, astrocyte-secreted apoE3 and E4 associated equally well with amyloid-beta. Under the same conditions, only a small fraction of A beta formed sodium dodecyl sulfate (SDS)-stable complexes with apoE (E3 > E4). These immortalized astrocytes will be useful for studying mechanisms underlying the isoform-specific effects of apoE in the CNS.

Amyloid beta-Peptides↗

PubMed2003

New roles for astrocytes: the nightlife of an 'astrocyte'. La vida loca!

Like a newly popular nightspot, the biology of adult stem cells has emerged from obscurity to become one of the most lively new disciplines of the decade. The neurosciences have not escaped this trendy pastime and, from amid the noise and excitement, the astrocyte emerges as a beguiling companion to the adult neural stem cell. A once receding partner to neurons and oligodendrocytes, the astrocyte even takes on an alter ego of the stem cell itself (S. Goldman, this issue of TINS). Putting ego aside, the 'astrocyte' is also (and perhaps more importantly) an integral component of neural progenitor hotspots, where the craziness or 'la vida loca' of the nightlife might not be so wild when compared with our traditional understanding of the astrocyte. Here, astrocytes contribute to the instructive confluence of location, atmosphere and cellular neighbors that define the daily 'vida local' or everyday local life of an adult stem cell. This review discusses astrocytes as influential components in the local stem cell niche.

Animals↗

PubMed2004

Astrocytic control of glutamatergic activity: astrocytes as stars of the show.

It is a major recent finding that astrocytes can influence synaptic activity by release of glutamate, but many other glutamate-mediated activities are also controlled by astrocytes. Even the most obvious neuronal function of glutamate - its release as a transmitter - is regulated by astrocytes; these cells are needed for formation of precursors for glutamate synthesis, for reuptake of released transmitter, and for disposal of excess glutamate. Without astrocytic involvement, normal function of glutamatergic neurons is not possible, as exemplified by almost instantaneous abrogation of normal vision and learning upon inhibition of astrocyte-specific metabolic pathways. In addition, astrocytes are essential for production of the neuroprotectant glutathione, yet they can also contribute to neuronal death during ischemia by maintaining glutamine synthesis, enabling neuronal formation of neurotoxic glutamate.

Animals↗

PubMed2000

Modulation of glial activation by astrocyte-derived protein S100B: differential responses of astrocyte and microglial cultures.

The astrocyte-derived protein S100B stimulates production of inducible nitric oxide synthase and nitric oxide (NO) in astrocytes [Hu et al., 1996, J. Biol. Chem. 271:2543], but its effect on microglia is not known. In addition, S100B's ability to modulate the activity of other glial activating agents has not been defined. In this study, we compared the ability of S100B to stimulate NO in cultures of rat primary astrocytes and the BV-2 murine microglial cell line, and investigated the effect of the combined action of S100B and other stimuli known to activate glial cells. S100B itself stimulated the production of NO in astrocytes, and did not modify or potentiated only weakly the NO production induced by interleukin-1 beta, tumor necrosis factor alpha, dibutyryl cyclic AMP, zymosan A or lipid A. In contrast, S100B alone did not induce NO in BV-2 cells but strongly potentiated NO production in the presence of lipid A but not zymosan A. The deletion of eight C-terminal amino acid residues in S100B leads to a loss of the effect of S100B on microglia but not on astrocytes. These results demonstrate that responses of glial cells to extracellular S100B can vary depending on the cell type, and suggest that different structural features of S100B are important for the protein's effects on microglia and astrocytes.

Amino Acid Sequence↗

PubMed1996

Exposure of astrocytes to hypoxia/reoxygenation enhances expression of glucose-regulated protein 78 facilitating astrocyte release of the neuroprotective cytokine interleukin 6.

Astrocytes exposed to hypoxia (H) or hypoxia/ reoxygenation (H/R) maintain cell viability and display changes in protein biosynthesis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of metabolically labeled astrocytes exposed to H showed induction of an approximately 78-kDa polypeptide that demonstrated sequence identity with glucose-regulated protein (GRP) 78. Cell lysates from H/R astrocytes displayed induction of neuroprotective interleukin (IL) 6, which was present in a high-molecular-weight complex also containing GRP78, suggesting that GRP78 might be functioning as a chaperone during cellular stress consequent on H/R. Introduction of antisense oligonucleotide to GRP78 into astrocytes prevented expression of the protein and suppressed H/R-induced astrocyte release of IL-6 by approximately 50%. These data indicate that modulation of astrocyte properties during oxygen deprivation results, in part, from intracellular glucose depletion and subsequent expression of GRP78, which sustains generation of neuroprotective IL-6 under the stress of H/R.

Animals↗

PubMed1997

beta-Adrenergic stimulation promotes homocysteic acid release from astrocyte cultures: evidence for a role of astrocytes in the modulation of synaptic transmission.

The sulfur-containing amino acid homocysteic acid (HCA) is present in and released from nervous tissue, exerting excitatory effects on neurons by predominantly activating NMDA receptors. It is interesting that HCA appears to be exclusively localized in glial cells, not in neurons. This profile of glial localization and excitatory action on neurons has led to the hypothesis that HCA could participate in intercellular communication in the brain as a "gliotransmitter." To test this hypothesis further, we searched for specific, receptor-mediated stimuli that could induce release of HCA from cultured astrocytes. For this reason we tested the effect of noradrenaline and vasoactive intestinal peptide, two transmitters known to interact with specific receptors on astrocytes, on the release of HCA from these cells. Noradrenaline and the beta-adrenergic agonist isoproterenol induced an efflux of HCA from astrocyte cultures. Further stressing the beta-adrenergic mediation of this effect is the blockade by atenolol of the HCA release evoked by isoproterenol. The stimulation of HCA release from astrocytes was not observed with the alpha-noradrenergic agonist methoxamine and with vasoactive intestinal peptide. These results taken together further strengthen the role of HCA as a gliotransmitter. Its efflux from glia could be controlled by noradrenaline, activating beta-adrenergic receptors on astrocytes. The present study provides the first evidence for an influence of beta-adrenergic receptor activation on the release of an excitatory amino acid from astrocytes and further supports the notion that glial-neuronal interactions play a role in synaptic transmission.

Adrenergic alpha-Agonists↗

PubMed2001

Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection.

It was recently proposed that in Jurkat cells, after inhibition of respiration by NO, glycolytically generated ATP plays a critical role in preventing the collapse of mitochondrial membrane potential (Deltapsi(m)) and thus apoptotic cell death. We have investigated this observation further in primary cultures of rat cortical neurons and astrocytes-cell types that differ greatly in their glycolytic capacity. Continuous and significant ( approximately 85%) inhibition of respiration by NO (1.4 microM at 175 microM O(2)) generated by [(z)-1-[2-aminoethyl]-N-[2-ammonioethyl]amino]diazen-1-ium-1,2 diolate (DETA-NO) initially (10 min) depleted ATP concentrations by approximately 25% in both cell types and increased the rate of glycolysis in astrocytes but not in neurons. Activation of glycolysis in astrocytes, as judged by lactate production, prevented further ATP depletion, whereas in neurons, which do not invoke this mechanism, there was a progressive decrease in ATP concentrations over the next 60 min. During this time, there was a persistent mitochondrial hyperpolarization and absence of apoptotic cell death in astrocytes, whereas in the neurons there was a progressive fall in Deltapsi(m) and increased apoptosis. After glucose deprivation or treatment with inhibitors of the F(1)F(0)-ATPase and adenine nucleotide translocase, astrocytes responded to NO with a fall in Deltapsi(m) and apoptotic cell death similar to the response in neurons. Finally, although treatment of astrocytes with NO partially prevented staurosporin-induced collapse in Deltapsi(m) and cell death, NO and staurosporin synergized in decreasing Deltapsi(m) and inducing apoptosis in neurons. These results demonstrate that although inhibition of cellular respiration by NO leads to neurotoxicity, it may also result in initial neuroprotection, depending on the glycolytic capacity of the particular cell.

Adenosine Triphosphate↗

PubMed2003

Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survival but induces potent neurotoxicity at distant sites via axonal transport.

The human immunodeficiency virus (HIV)-Tat protein has been implicated in the neuropathogenesis of HIV infection. However, its role in modulating astroglial-neuronal relationships is poorly understood. Astrocyte infection with HIV has been associated with rapid progression of dementia. We thus initially transfected astrocytes with HIV proviral DNA and confirmed Tat production in these cells. Subsequently, using stably Tat-producing asytocyte cell lines, we observed that Tat promoted astrocyte survival by causing a prominent antioxidant effect and resistance to cell injury in these cells. Tat was released extracellularly where it could be taken up by other cells. Tat remained functionally active following uptake and caused long terminal repeat (LTR) transactivation in lymphocytic and astrocytic cell lines. Tat released from astrocytes caused mitochondrial dysfunction, trimming of neurites, and cell death in neurons. Tat neurotoxicity was attenuated by anti-Tat antibodies, kynurenate or heparan sulfate. The neurotoxic effects of Tat were caused at concentrations lower than that needed to cause LTR transactivation. When Tat-expressing cells were injected into the rat dentate gyrus, Tat was taken up by granule cells and transported along neuronal pathways to the CA3 region where it caused glial cell activation and neurotoxicity. The arginine-rich domain of Tat was essential for both the LTR transactivation and the neurotoxic properties of Tat. Thus HIV-Tat is a potent neurotoxin that may act at distant sites while at the same time it assures its production by preventing cell death in astrocytes where it is produced.

Astrocytes↗

PubMed2001

HIV-1 Nef co-localizes with the astrocyte-specific cytoskeleton protein GFAP in persistently nef-expressing human astrocytes.

In T-cells HIV-1 Nef exerts various functions and interacts with actin. In astrocytes interaction of Nef with cellular proteins is poorly understood. Therefore, human astrocytic cell clones stably transfected with nef-genes derived from HIV-1 Bru and its myristoylation-defective TH-variant were investigated by confocal laser scanning microscopy for expression of Nef and cytoskeleton proteins actin and GFAP, a marker for activated astrocytes. Myristoylated Nef was detected in cytoplasm, Golgi and plasmamembrane, while non-myristoylated Nef was exclusively cytoplasmic. Nef co-localised with GFAP in the perinuclear region of astrocytes. In contrast, Nef did not interact with actin filaments in human astrocytes. Nef/GFAP interaction could contribute to changes in morphology and activation state of astrocytes shown previously which are both critical for development of astrogliosis in HIV-1 infected brain.

Actins↗

PubMed1991

Localization of the CD44 glycoprotein to fibrous astrocytes in normal white matter and to reactive astrocytes in active lesions in multiple sclerosis.

The CD44 antigen is a proteoglycan recently implicated in several adhesion events including that of lymphocytes to endothelium. The CD44 antigen, reactive with monoclonal antibody (MAb) 44D10, has been shown previously to be expressed in normal human white matter homogenates and to be found at higher concentrations in brain homogenates of victims of multiple sclerosis (MS). The cellular localization of CD44 in human brain of normal individuals and in those afflicted with MS has now been determined. Monoclonal antibody 44D10 reacted with astrocyte-like cells in 40 microns thick paraformaldehyde-fixed sections but not in thin (6 microns) fixed sections. A double labeling experiment performed on a frozen brain section with MAb 44D10 and rabbit anti-glial fibrillary acidic protein (GFAP), a cytoplasmic marker of astrocytes, confirmed the co-localization of these two antigens. The reactivity with brain tissue sections of a rabbit antiserum produced against lymphocyte-CD44 could be absorbed by a preparation of the CD44 glycoprotein, purified 2,100-fold from a white matter homogenate. The antiserum was shown by Western blot analysis to be specific for p80 glycoprotein in brain extracts derived from a normal and MS patients. This antibody reacted with fibrous astrocytes predominantly in white matter; staining was also noted in subependymal and subpial regions. Inhibition studies using a cellular radioimmunoassay indicated that the highest concentrations of CD44 in three MS victims were found in plaques, followed by periplaques and non-involved areas of white matter which were higher than normal white matter. Reactive astrocytes, identified in active lesions, expressed high levels of CD44 on their surfaces. Thus, CD44 is associated with astrocytes in human brain and the increased expression observed in MS brain may reflect activation and/or proliferation of astrocytes implicated in the pathogenesis of this disease.

Astrocytes↗

PubMed2001

PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo.

We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a-Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-B into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-B caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.

Animals↗

PubMed1995

Increased beta-amyloid precursor protein expression in astrocytes in the gerbil hippocampus following ischaemia: association with proliferation of astrocytes.

Increases in beta-amyloid precursor proteins (APP), which include the beta-amyloid senile plaque protein present in patients with Alzheimer's disease, have been shown to occur in models of neuronal damage and neurotoxic cell injury. This observation led us to examine the expression of these proteins after transient ischaemic episodes in the gerbil. Animals were killed 2-28 days after ischaemia and APP were detected by immunocytochemistry at the light and electron microscopic levels with an antibody raised against the C-terminal region of these proteins. The gliotic reaction was also examined using glial fibrillary acid protein (GFAP) immunoreactivity. Two days after ischaemia, neuronal cell death was observed in the hippocampal CA1 region accompanied by astrocyte hypertrophy. These hypertrophic astrocytes were found to be GFAP positive but stained weakly for APP. Seven days after ischaemia both astrocyte hypertrophia and hyperplasia, with identified mitotic figures, were observed. These hyperplasic astrocytes were intensely stained by the APP antibody, and were observed up to 28 days after ischaemia. This shows that neuronal cell death produced by transient ischaemia is followed by an increased APP expression which appears to be associated with the hyperplasic astrocytes but not with the initial hypertrophy of this cell population. These results, when taken together with those obtained in other models of neuronal damage or death, clearly suggest that APP expression follows neuronal death and is associated with astrocyte proliferation.

Amyloid beta-Protein Precursor↗

PubMed2003

A role for hypertrophic astrocytes and astrocyte precursors in a case of rapidly progressive multiple sclerosis.

The purpose of this study was to examine the roles played by astrocytes in a case of rapidly progressive multiple sclerosis (MS). Within early-active and active lesions, hypertrophic astrocytes played an important role in lesion pathology through the phagocytosis of myelin and axonal debris and through the internalization of other glial cells, including astrocytes. In addition to this critical role, hypertrophic astrocytes, in areas that lack significant inflammation (within the adjacent normal appearing white matter and within late remyelinating lesions) were found to be active in myelin and axonal debris phagocytosis with no evidence of cellular internalization. Hypertrophic astrocytes therefore not only play an important role in the pathogenesis of MS lesions but also exert a continued deleterious effect upon tissue in the absence of significant inflammation. In addition, we found evidence for a significant population of vimentin-positive, glial fibrillary acidic protein (GFAP)-negative, bipolar, astrocyte precursors within the late remyelinating lesions. Their significance is not known but a possible role may include their participation in the successful remyelination of the lesion.

Astrocytes↗

PubMed2003

Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains.

The postnatal central nervous system (CNS) contains many scattered cells that express fibroblast growth factor receptor 3 transcripts (Fgfr3). They first appear in the ventricular zone (VZ) of the embryonic spinal cord in mid-gestation and then distribute into both grey and white matter - suggesting that they are glial cells, not neurones. The Fgfr3(+) cells are interspersed with but distinct from platelet-derived growth factor receptor alpha (Pdgfra)-positive oligodendrocyte progenitors. This fits with the observation that Fgfr3 expression is preferentially excluded from the pMN domain of the ventral VZ where Pdgfra(+) oligodendrocyte progenitors--and motoneurones--originate. Many glial fibrillary acidic protein (Gfap)- positive astrocytes co-express Fgfr3 in vitro and in vivo. Fgfr3(+) cells within and outside the VZ also express the astroglial marker glutamine synthetase (Glns). We conclude that (1) Fgfr3 marks astrocytes and their neuroepithelial precursors in the developing CNS and (2) astrocytes and oligodendrocytes originate in complementary domains of the VZ. Production of astrocytes from cultured neuroepithelial cells is hedgehog independent, whereas oligodendrocyte development requires hedgehog signalling, adding further support to the idea that astrocytes and oligodendrocytes can develop independently. In addition, we found that mice with a targeted deletion in the Fgfr3 locus strongly upregulate Gfap in grey matter (protoplasmic) astrocytes, implying that signalling through Fgfr3 normally represses Gfap expression in vivo.

Animals↗

PubMed2006

Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury.

Modulating the behaviors of reactive astrocytes is a potential therapeutic strategy for neurodegenerative diseases. We found that upregulation and activation of the epidermal growth factor receptor (EGFR) occur in astrocytes after different injuries in optic nerves in vivo. Activation of EGFR regulates genes and cellular processes representing most major markers of reactive astrocytes and genes related with glaucomatous optic neuropathy and other neural disorders. These results suggest that activation of EGFR is a common, regulatory pathway that triggers quiescent astrocytes into reactive astrocytes in response to neural injuries in the optic nerve, and perhaps other parts of the CNS. Targeting EGFR activation using an EGFR tyrosine kinase inhibitor prevents the loss of retinal ganglion cells in a model of glaucomatous optic neuropathy. Because these inhibitors are currently used clinically, our results present an approach to reactive astrocytes as a potential new target for the treatment of neurodegenerations.

Animals↗