Astrocyte Research Papers - Academia.edu (original) (raw)
but much less in those that have reached the olfactory bulb. We show that two of the naturally occurring Notch1 activators, Jagged1 and Delta1, are also expressed in the SVZ and within the RMS in the adult mouse brain. Finally, using a... more
but much less in those that have reached the olfactory bulb. We show that two of the naturally occurring Notch1 activators, Jagged1 and Delta1, are also expressed in the SVZ and within the RMS in the adult mouse brain. Finally, using a model of cortical stab wound, we show that the astrogliogenic response of the SVZ to injury is accompanied by activation of the Notch pathway.
The derivation of neural progenitor cells from human embryonic stem (ES) cells is of value both in the study of early human neurogenesis and in the creation of an unlimited source of donor cells for neural transplantation therapy. Here we... more
The derivation of neural progenitor cells from human embryonic stem (ES) cells is of value both in the study of early human neurogenesis and in the creation of an unlimited source of donor cells for neural transplantation therapy. Here we report the generation of enriched and expandable preparations of proliferating neural progenitors from human ES cells. The neural progenitors could
Epidemiological studies have shown that steroidal as well as non-steroidal anti-inflammatory drugs lower the risk of developing Ž . Alzheimer's Disease AD . A suppressive effect of these anti-inflammatory drugs on local inflammatory... more
Epidemiological studies have shown that steroidal as well as non-steroidal anti-inflammatory drugs lower the risk of developing Ž . Alzheimer's Disease AD . A suppressive effect of these anti-inflammatory drugs on local inflammatory events in AD brains has been suggested, however the mechanisms responsible are still unknown. In this study we investigated at cellular level the influence of two anti-inflammatory drugs-dexamethasone and indomethacin-and an experimental specific cyclooxygenase-2 inhibitor, BF389, on the production of the pro-inflammatory cytokine IL-6 and the inflammatory mediator PGE by human astrocytes. Two human post-mortem 2 2 2 of these drugs in AD. q 1997 Elsevier Science B.V.
Neural probes are micromachined multichannel electrode arrays that facilitate the functional stimulation and recording of neurons in the peripheral and central nervous system. For long-term implantations, surface modification is necessary... more
Neural probes are micromachined multichannel electrode arrays that facilitate the functional stimulation and recording of neurons in the peripheral and central nervous system. For long-term implantations, surface modification is necessary for maintaining the stable connection between electrodes and neurons. The conductive polymer polypyrrole (PPy) and synthetic peptide DCDPGYIGSR were co-deposited on the electrode surface by electrochemical polymerization. The stability of PPy/ DCDPGYIGSR coatings was tested in soaking experiments. It was found that the peptide was entrapped in the PPy film and did not diffuse away within 7 weeks of soaking in DI water. Coated probes were implanted in guinea pig brain for periods of 1, 2 and 3 weeks. Recording tests were performed and the impedance was monitored. The explanted probes and tissue were examined by immunocytochemical studies. Significantly more neurofilament positive staining was found on the coated electrode which indicated that the coatings had established strong connections with the neuronal structure in vivo. Good recordings were obtained from the coated sites that had neurons attached. First week tissue sections had no significant gliosis. In week 2, a layer of non-neuronal tissue consisting of mostly meningeal fibroblasts and ECM protein including at least fibronectin was formed around the probe tracks of both coated and uncoated probes. Astrocytes started to form a loosely organized layer by the end of the third week. r
A three-layered backpropagation neural network was developed to differentiate malignant from benign brain tumors in a group of patients with astrocytic gliomas. The MRI findings of 43 patients were reviewed before biopsy by three... more
A three-layered backpropagation neural network was developed to differentiate malignant from benign brain tumors in a group of patients with astrocytic gliomas. The MRI findings of 43 patients were reviewed before biopsy by three neuroradiologists independently. This provided a database made up of 129 patients' records each of which comprised I3 parameters derived from pre-and post-contrast MR images. The network's generalizing ability was then tested to predict the outcome of biopsy in 36 new cases and its performance compared to that of radiologist using ROC analysis. The output of the network with and without radiologists' impression yielded a better diagnostic performance with relative ROC areas of 0.94 and 0.9 1. respectively, compared to 0.84 obtained by radiologist. These results demonstrate that the neural network can effectively differentiate malignant from benign brain tumors.
Background: The objectives of the study were to characterize the expression of the αand β-subunits of granulocyte-macrophage colony stimulating factor (GM-CSF) receptor in bovine cumulus cells and oocytes and to determine the effect of... more
Background: The objectives of the study were to characterize the expression of the αand β-subunits of granulocyte-macrophage colony stimulating factor (GM-CSF) receptor in bovine cumulus cells and oocytes and to determine the effect of exogenous GM-CSF on cumulus cells expansion, oocyte maturation, IGF-2 transcript expression and subsequent competence for embryonic development.
The differentiation and proliferation of neural stem/progenitor cells (NPCs) depend on various in vivo environmental factors or cues, which may include an endogenous electrical field (EF), as observed during nervous system development and... more
The differentiation and proliferation of neural stem/progenitor cells (NPCs) depend on various in vivo environmental factors or cues, which may include an endogenous electrical field (EF), as observed during nervous system development and repair. In this study, we investigate the morphologic, phenotypic, and mitotic alterations of adult hippocampal NPCs that occur when exposed to two EFs of estimated endogenous strengths. NPCs treated with a 437 mV/mm direct current (DC) EF aligned perpendicularly to the EF vector and had a greater tendency to differentiate into neurons, but not into oligodendrocytes or astrocytes, compared to controls. Furthermore, NPC process growth was promoted perpendicularly and inhibited anodally in the 437 mV/mm DC EF. Yet fewer cells were observed in the DC EF, which in part was due to a decrease in cell viability. The other EF applied was a 46 mV/mm alternating current (AC) EF. However, the 46 mV/mm AC EF showed no major differences in alignment or differentiation, compared to control conditions. For both EF treatments, the percent of mitotic cells during the last 14 h of the experiment were statistically similar to controls. Reported here, to our knowledge, is the first evidence of adult NPC differentiation affected in an EF in vitro. Further investigation and application of EFs on stem cells is warranted to elucidate the utility of EFs to control phenotypic behavior. With progress, the use of EFs may be engineered to control differentiation and target the growth of transplanted cells in a stem cell-based therapy to treat nervous system disorders.
Astroglia and steroid hormones such as estrogen and progesterone regulate cell growth, function, and protection in the central nervous system (CNS). It appears that astrocytes and steroids act in concert to promote cell survival under... more
Astroglia and steroid hormones such as estrogen and progesterone regulate cell growth, function, and protection in the central nervous system (CNS). It appears that astrocytes and steroids act in concert to promote cell survival under pathological conditions. With respect to the role of mitochondrial fusion and fission in energy metabolism, apoptosis, and proliferation, astrocyte mitochondria resemble a perfect intracellular target for steroids to modulate these processes, thereby promoting cell vitality after damage. We have studied the effects of estrogen and progesterone on cell viability in comparison with mitochondrial fusion and fission gene transcription in primary cortical astrocytes from female and male mouse brains. Estrogen-and progesterone-treated female astrocytes demonstrated an increase in cell number and proliferation marker accompanied by an upregulation of fusion and fission gene transcription, which were apparently balancing pro-and anti-apoptotic processes. On the other hand, male astrocytes exhibited no change in cell number after estrogen treatment, but a decrease after progesterone administration. This could be the consequence of stimulated apoptosis in male astrocytes by both steroids, which was counterbalanced by an increased proliferation in the presence of estrogen, whereas it was strengthened in the presence of progesterone. Supportively, estrogen promoted and progesterone decreased the transcription of fusion and fission genes. We suggest that estrogen and progesterone affect mitochondrial fusion and fission gene transcription in cortical astrocytes in a gender-specific way, thereby influencing mitochondrial function differently in both genders. Thus, interaction of sex steroids with mitochondria may represent one possible cause for gender differences in cellular pathology in the CNS.
For the purpose of studying the potential neurobehavioral effects of different human apolipoprotein E (apoE) isoforms produced within the brain, transgenic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control... more
For the purpose of studying the potential neurobehavioral effects of different human apolipoprotein E (apoE) isoforms produced within the brain, transgenic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control of an astrocyte-specific, glial fibrillary acidic protein promoter and these TG mice were bred back to apoE knockout (KO) mice. Behavioral phenotypes of apoE3 and apoE4 TG mice were derived by conducting a longitudinal study in which apoE3 and apoE4 TG mice were compared with apoE KO and wild-type (WT) mice (all male) on several behavioral measures. Analysis of locomotor activity, "open-field" behaviors, acoustic startle/prepulse inhibition, and elevated plus maze data suggested that the apoE TG/KO groups were more "emotionally reactive" than WT mice, with apoE4 mice typically being the most reactive. The absence of performance differences among groups on the rotating holeboard and water navigation tasks suggested intact reference memory processing in apoE TG/KO mice. However, apoE4 mice were profoundly impaired on a working memory-based protocol in the radial arm maze (11-14 months). Nonassociative factors (sensorimotor capacities or emotionality differences) did not appear to confound interpretation of the learning/memory results. Western blot analysis revealed no alterations in the level of synaptic, neuronal, or glial markers in neocortex or hippocampus and histologic analysis revealed no evidence of Abeta deposition or neuritic plaques in the apoE KO/TG mice. Our findings suggest that apoE4 expression in the brain may have selective deleterious effects on memory function in the absence of typical Alzheimer's-like neuropathology.
The hypothalamic suprachiasmatic nuclei (SCN), the site of a mammalian circadian clock, exhibit a dense immunoreactivity for glial fibrillary acidic protein (GFAP), a specific marker for astrocytes. Although there is evidence of a... more
The hypothalamic suprachiasmatic nuclei (SCN), the site of a mammalian circadian clock, exhibit a dense immunoreactivity for glial fibrillary acidic protein (GFAP), a specific marker for astrocytes. Although there is evidence of a circadian variation in GFAP-IR in the hamster SCN and of the participation of glial cells in input and output mechanisms of the clock, the role of these cells within the circadian system is not clearly understood. The fact that astroglia can express and respond to cytokines suggests that they could work as mediators of immune signals to the circadian system. In the present study, we have found a daily variation of GFAP-IR in the mouse SCN, peaking during the light phase. In addition, we have identified GFAP and nuclear factor-jB (NF-jB) in glial cells within the SCN and in primary cultures of the mouse SCN. Moreover, SCN glia cultures were transfected with an NF-jB/luc construct whose transcriptional activity was increased with lipopolysaccharide 2 lg/ml, tumor necrosis factor-a 20 ng/ml, or interleukin-1a 100 ng/ ml, after 12 hr of stimulation. These results suggest that the glial cells of the SCN can mediate input signals to the mouse circadian system coming from the immune system via NF-jB signaling. V V C 2006 Wiley-Liss, Inc.
- by Diego Golombek and +1
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- Neuroscience, Psychology, Signal Transduction, Mice
Rotenone, a mitochondrial complex 1 inhibitor, causes oxidative damage via production of reactive oxygen species. We examined the pathophysiology of neuronal and glial cells of the nigrostriatal pathway following unilateral infusion of... more
Rotenone, a mitochondrial complex 1 inhibitor, causes oxidative damage via production of reactive oxygen species. We examined the pathophysiology of neuronal and glial cells of the nigrostriatal pathway following unilateral infusion of varying doses of rotenone into the substantia nigra or medial forebrain bundle of adult male Sprague-Dawley rats, sacrificed 14 and 60 days after infusion. Immunofluorescence techniques were used to qualitatively and quantitatively assay dopaminergic neurons, their projections, glial cells, synapses, and oxidative stress. Rotenone infusion into the substantia nigra at all concentrations caused extensive damage and tissue necrosis, therefore of limited relevance for producing a Parkinson disease model. Infusion of 0.5 μg of rotenone targeting the medial forebrain bundle induced oxidative stress in dopaminergic neurons causing ongoing cell stress as defined by an elevation of stress granule and oxidative stress markers. This treatment resulted in the loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (p ≤ 0.01) and loss of tyrosine hydroxylase immunoreactive nerve fibres and synaptic specialisations in the striatum (p ≤ 0.01). The infusion of 0.5 μg of rotenone also caused an increase in astrocytes and microglial cells in the substantia nigra in comparison to control (p ≤ 0.01). We examined the time-dependent reduction of tyrosine hydroxylase-positive nerve fibres and cell bodies in the striatum and substantia nigra respectively, with a progressive reduction evident 60 days after infusion (p ≤ 0.01, p ≤ 0.05). Dopaminergic axons exposed to low-dose rotenone undergo oxidative stress, with a resultant ongoing loss of dopaminergic neurons, providing an animal model relevant to Parkinson disease.
In the central nervous system, astrocytes form an intimately connected network with neurons, and their processes closely enwrap synapses. The critical role of these cells in metabolic and trophic support to neurons, ion buffering and... more
In the central nervous system, astrocytes form an intimately connected network with neurons, and their processes closely enwrap synapses. The critical role of these cells in metabolic and trophic support to neurons, ion buffering and clearance of neurotransmitters is well established. However, recent accumulating evidence suggests that astrocytes are active partners of neurons in additional and more complex functions. In particular, astrocytes express a repertoire of neurotransmitter receptors mirroring that of neighbouring synapses. Such receptors are stimulated during synaptic activity and start calcium signalling into the astrocyte network. Intracellular oscillations and intercellular calcium waves represent the astrocyte’s own form of excitability, as they trigger release of transmitter (i.e. glutamate) via a novel process sensitive to blockers of exocytosis and involving cyclooxygenase eicosanoids. Astrocyte-released glutamate activates receptors on the surrounding neurons and modifies their electrical and intracellular calcium ([Ca2+]i) state. These exciting new findings reveal an active participation of astrocytes in synaptic transmission and the involvement of neuron-astrocyte circuits in the processing of information in the brain.
We and others have previously shown that heat-shock proteins (HSPs) are involved in protecting the brain from a variety of insults including stroke, epilepsy, and other related insults. While the mechanism of this protection has largely... more
We and others have previously shown that heat-shock proteins (HSPs) are involved in protecting the brain from a variety of insults including stroke, epilepsy, and other related insults. While the mechanism of this protection has largely been thought to be due to their chaperone functions (i.e., preventing abnormal protein folding or aggregation), recent work has shown that HSPs may also directly interfere with other cell death pathways such as apoptosis and inflammation. Using models of cerebral ischemic and ischemia-like injury, we overexpressed the 70-kDa heat-shock protein (HSP70) using gene transfer or by studying a transgenic mouse model. HSP70 protected neurons and astrocytes from experimental stroke and stroke-like insults. HSP70 transgenic mice also had better neurological scores following experimental stroke compared to their wild-type littermates. Overexpressing HSP70 was associated with less apoptotic cell death and increased expression of the antiapoptotic protein, Bcl-2. Furthermore, HSP70 suppressed microglial/monocyte activation following experimental stroke. HSP70 overexpression also led to the reduction of matrix metalloproteinases. We suggest that HSPs are capable of protecting brain cells from lethal insults through a variety of mechanisms and should be explored as a potential therapy against stroke and other neurodegenerative diseases.
Olfactory ensheathing cells (OECs) accompany the axons of olfactory receptor neurons, which regenerate throughout life, from the olfactory mucosa into the olfactory bulb. OECs have shown widely varying efficacy in repairing the injured... more
Olfactory ensheathing cells (OECs) accompany the axons of olfactory receptor neurons, which regenerate throughout life, from the olfactory mucosa into the olfactory bulb. OECs have shown widely varying efficacy in repairing the injured nervous system. Analysis of the transcriptome of OECs will help in understanding their biology and will provide tools for investigating the mechanisms of their efficacy and interactions with host tissues in lesion models. In this study, we compared the transcriptional profile of cultured OECs with that of Schwann cells (SCs) and astrocytes (ACs), two glial cell types to which OECs have similarities. Two biological replicates of RNA from cultured OECs, SCs, and ACs were hybridized to long oligo rat 5K arrays against a common reference pool of RNA (50% cultured fibroblast RNA and 50% neonatal rat brain RNA). Transcriptional profiles were analyzed by hierarchical clustering, Principal Components Analysis, and the Venn diagram. The three glial cell types had similarly increased or decreased expression of numerous transcripts compared with the reference. However, OECs were distinguishable from both SCs and ACs by a modest number of transcripts, which were significantly enriched or depleted. Furthermore, OECs and SCs were more closely related to each other than to ACs. Expression of selected transcripts not previously characterized in OECs, such as Lyz, Timp2, Gro1 (Cxcl1), Ccl2 (MCP1), Ctgf, and Cebpb, was validated by real-time reverse transcription-polymerase chain reaction (RT-PCR); immunohistochemistry in cultured OECs, SCs, and ACs, and adult tissues was performed to demonstrate their expression at the protein level. in Wiley InterScience (www.interscience.wiley. com).
- by Adrian West and +2
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- Genetics, Immunohistochemistry, Gene expression, Astrocyte
Competition between glucose and lactate as oxidative energy substrates was investigated in both primary cultures of astrocytes and neurons using physiological concentrations (1.1 mm for each). Glucose metabolism was distinguished from... more
Competition between glucose and lactate as oxidative energy substrates was investigated in both primary cultures of astrocytes and neurons using physiological concentrations (1.1 mm for each). Glucose metabolism was distinguished from lactate metabolism by using alternatively labelled substrates in the medium ([1-13 C]glucose + lactate or glucose + [3-13 C]lactate). After 4 h of incubation, 1 H and 13 C-NMR spectra were realized on perchloric acid extracts of both cells and culture media. For astrocytic cultures, spectra showed that amino acids (glutamine and alanine) were more labelled in the glucose-labelled condition, indicating that glucose is a better substrate to support oxidative metabolism in these cells. The opposite was observed on spectra from neuronal cultures, glutamate being much more labelled in the lactate-labelled condition, confirming that neurons consume lactate preferentially as an oxidative energy substrate. Analysis of glutamine and glutamate peaks (singlets or multiplets) also suggests that astrocytes have a less active oxidative metabolism than neurons. In contrast, they exhibit a stronger glycolytic metabolism than neurons as indicated by their high lactate production yield. Using a mathematical model, we have estimated the relative contribution of exogenous glucose and lactate to neuronal oxidative metabolism. Under the aforementioned conditions, it represents 25% for glucose and 75% for lactate. Altogether, these results obtained on separate astrocytic and neuronal cultures support the idea that lactate, predominantly produced by astrocytes, is used as a supplementary fuel by neurons in vivo already under resting physiological conditions.
Chemokines have been involved in cellular processes associated to malignant transformation such as proliferation, migration and angiogenesis. The expression of five CXC chemokine receptors and their main ligands was analysed by RT-PCR in... more
Chemokines have been involved in cellular processes associated to malignant transformation such as proliferation, migration and angiogenesis. The expression of five CXC chemokine receptors and their main ligands was analysed by RT-PCR in 31 human astrocytic neoplasms. The mRNAs for all the receptors analysed were identified in a high percentage of tumours, while their ligands showed lower expression. CXCR4 and SDF1 were the most frequently mRNA identified (29/31 and 13/31 of the gliomas studied, respectively). Thus, we further analysed the cell localization of CXCR4 and SDF1 in immunohistochemistry experiments. We show a marked co-localization of CXCR4 and SDF1 in tumour cells, mainly evident in psudolpalisade and microcystic degeneration areas and in the vascular endothelium. In addition, hSDF1α induced a significant increase of DNA synthesis in primary human glioblastoma cell cultures and chemotaxis in a glioblastoma cell line.These results provide evidence of the expression of multiple CXC chemokines and their receptors in brain tumours and that in particular CXCR4 and SDF1 sustain proliferation and migration of glioma cells to promote malignant progression.
- by Antonio Daga and +1
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- Neurochemistry, Cell Migration, Immunohistochemistry, Cell Culture
Our previous research effort has resulted in a stochastic model that provides an excellent fit to our experimental data on proliferation and differentiation of oligodendrocyte type-2 astrocyte progenitor cells at the clonal level.... more
Our previous research effort has resulted in a stochastic model that provides an excellent fit to our experimental data on proliferation and differentiation of oligodendrocyte type-2 astrocyte progenitor cells at the clonal level. However, methods for estimation of model parameters and their statistical properties still remain far away from complete exploration. The main technical difficulty is that no explicit analytic expression for the joint distribution of the number of progenitor cells and oligodendrocytes, and consequently for the corresponding likelihood function, is available. In the present paper, we overcome this difficulty by using computer-intensive simulation techniques for estimation of the likelihood function. Since the output of our simulation model is essentially random, stochastic optimization methods are necessary to maximize the estimated likelihood function. We use the Kiefer–Wolfowitz procedure for this purpose. Given sufficient computing resources, the proposed estimation techniques significantly extend the spectrum of problems that become approachable. In particular, these techniques can be applied to more complex branching models of multi-type cell systems with dependent evolutions of different types of cells.
Ammonia is a major neurotoxin implicated in hepatic encephalopathy (HE). Here we discuss evidence that many aspects of ammonia toxicity in HE-affected brain are mediated by glutamine (Gln), synthesized in excess from ammonia and glutamate... more
Ammonia is a major neurotoxin implicated in hepatic encephalopathy (HE). Here we discuss evidence that many aspects of ammonia toxicity in HE-affected brain are mediated by glutamine (Gln), synthesized in excess from ammonia and glutamate by glutamine synthetase (GS), an astrocytic enzyme. The degree to which Gln is increased in brains of patients with HE was found to positively correlate with the grade of HE. In animals with HE, a GS inhibitor, methionine sulfoximine (MSO), reversed a spectrum of manifestations of ammonia toxicity, including brain edema and increased intracranial pressure, even though MSO itself increased brain ammonia levels. MSO inhibited, while incubation with Gln reproduced the oxidative stress and cell swelling observed in ammonia-exposed cultured astrocytes. Recent studies have shown that astrocytes swell subsequent to Gln transport into mitochondria and its degradation back to ammonia, which then generates reactive oxygen species and the mitochondrial permeability transition. This sequence of events led to the formulation of the "Trojan Horse" hypothesis. Further verification of the role of Gln in the pathogenesis of HE will have to account for: 1) modification of the effects of Gln by interaction of astrocytes with other CNS cells; and 2) direct effects of Gln on these cells. Recent studies have demonstrated a "Trojan Horse"-like effect of Gln in microglia, as well as an interference by Gln with the activation of the NMDA/NO/cGMP pathway by ammonia as measured in whole brain, a process that likely also involves neurons.
Abstract: The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. ▵9-Tetrahydrocannabinol (THC), the major active component of marijuana, produced a malonyl-CoA-independent stimulation of carnitine... more
Abstract: The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. ▵9-Tetrahydrocannabinol (THC), the major active component of marijuana, produced a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I (CPT-I) and ketogenesis from [14C]palmitate. The THC-induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU-210 and was prevented by pertussis toxin and the CB1 cannabinoid receptor antagonist SR141716. Experiments performed with different cellular modulators indicated that the THC-induced stimulation of ketogenesis was independent of cyclic AMP, Ca2+, protein kinase C, and mitogen-activated protein kinase (MAPK). The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied. THC produced a CB1 receptor-dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels. Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK-independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC. Furthermore, ceramide activated CPT-I in astrocyte mitochondria. Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on CB1 receptor activation, sphingomyelin hydrolysis, and ceramide-mediated activation of CPT-I.
During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by... more
During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.
Phenolic composition of wine depends not only on the grape variety from which it is made, but on some external factors such as winemaking technology. Red wine possesses the most antioxidant effect because of its high polyphenolic content.... more
Phenolic composition of wine depends not only on the grape variety from which it is made, but on some external factors such as winemaking technology. Red wine possesses the most antioxidant effect because of its high polyphenolic content. The aim of this work is to study for the first time, the neuroprotective activity of four monovarietal Spanish red wines (Merlot (ME), Tempranillo (T), Garnacha (G) and Cabernet-Sauvignon (CS)) through its antioxidant ability, and to relate this neuroprotection to its polyphenolic composition, if possible. The wine effect on neuroprotection was studied through its effect as free radical scavenger against FeSO 4 , H 2 O 2 and FeSO 4 + H 2 O 2 . Effect on cell survival was determined by 3(4,5dimethyltiazol-2-il)-2,5-diphenyltetrazolium reduction assay (MTT) and lactate dehydrogenase (LDH) release assay on astrocytes cultures. Results showed that most of the studied wine varieties induced neuroprotection through their antioxidant ability in astrocytes, Merlot being the most active; this variety is especially rich in phenolic compounds, mainly catechins and oligomeric proanthocyanidins. Our results show that red wine exerts a protection against oxidative stress generated by different toxic agents and that the observed neuroprotective activity is related to their polyphenolic content.
- by M. Gómez-Serranillos and +1
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- Flavonoids, Wine, Antioxidants, Polyphenols
Bcl-2 proto-oncogene prevents apoptosis in many conditions. First detected in lymphomas, it has been also described in non-lymphoid tissues. The immunohistochemical distribution of bcl-2 protein in 100 neuroepithelial tumors is presented.... more
Bcl-2 proto-oncogene prevents apoptosis in many conditions. First detected in lymphomas, it has been also described in non-lymphoid tissues. The immunohistochemical distribution of bcl-2 protein in 100 neuroepithelial tumors is presented. Bcl-2 was positive in some neurons of normal nervous tissue, in reactive astrocytes and variably in all neuroepitelial tumors. The reaction product was either diffuse or granular, due to bcl-2 protein localization on cytoplasmic, nuclear and mitochondrial membranes. The positivity was high in medulloblastomas and in astrocytic tumors. In the latter, the strongest staining was found in cells retaining the astrocytic aspect. Oligodendroglial cells were minimally stained.
Summary: We report a case of a hypothalamic chiasmatic ganglioglioma in a 21-year-old woman who presented with hyperprolactinemia and developed visual field defects. This circumscribed cystic lesion with an enhancing mural nod- ule was... more
Summary: We report a case of a hypothalamic chiasmatic ganglioglioma in a 21-year-old woman who presented with hyperprolactinemia and developed visual field defects. This circumscribed cystic lesion with an enhancing mural nod- ule was radiologically indistinguishable from a pilocytic as- trocytoma. Although rare, gangliogliomas should be in- cluded in the differential diagnosis of lesions occurring in this area of the brain. Gangliogliomas, although relatively rare, are the most frequently occurring mixed glioneuronal tu- mors of the CNS (1). Their incidence ranges from 0.4% to 1.3% of all brain tumors, but they are more common in the pediatric group, with an incidence of 7.6% (2, 3). Patients usually present with sei- zures (2). The temporal lobes are the most common site, but gangliogliomas can occur anywhere in the central neuraxis, including the brain stem and spi- nal cord (1). We report a case of a ganglioglioma arising in the hypothalamic chiasmatic region and its MR imaging...
Extracellular adenosine (Ado) and ATP stimulate astrocyte proliferation through activation of P 1 and P 2 purinoceptors. Extracellular GTP and guanosine (Guo), however, that do not bind strongly to these receptors, are more effective... more
Extracellular adenosine (Ado) and ATP stimulate astrocyte proliferation through activation of P 1 and P 2 purinoceptors. Extracellular GTP and guanosine (Guo), however, that do not bind strongly to these receptors, are more effective mitogens than ATP and Ado. Exogenous Guo, like GTP and 5Ј-guanosine-␥-imidotriphosphate (GMP-PNP), dose-dependently stimulated proliferation of rat cultured astrocytes; potency order GMP-PNP Ͼ GTP Ն Guo. The mitogenic effect of Guo was independent of the extracellular breakdown of GTP to Guo, because GMP-PNP, a GTP analogue resistant to hydrolysis, was the most mitogenic. In addition to a direct effect on astrocytes, Guo exerts its proliferative activity involving Ado. Exogenous Guo, indeed, enhanced the extracellular levels of endogenous Ado assayed by HPLC in the medium of cultured astrocytes. Culture pretreatment with Ado deaminase (ADA), that converts Ado into inosine, reduced but did not abolish Guo-induced astrocyte proliferation whereas erythro-9-(2hydroxy-3-nonyl)adenine (EHNA), that inhibits ADA activity, amplified Guo effect. Moreover, the mitogenic activity of Guo was partly inhibited by 8-cyclopentyl-1,3dipropylxanthine and alloxazine, antagonists of Ado A 1 and A 2B receptors, respectively. Also microglia seem to be a target for the action of Guo. Indeed, the mitogenic effect of Guo on astrocytes was: i) increased proportionally to the number of microglial cells present in the astrocyte cultures; ii) amplified when purified cultures of astrocytes were supplemented with conditioned medium deriving from Guo-pretreated microglial cultures. These data indicate that the mitogenic effects exerted by exogenous Guo on rat astrocytes are mediated via complex mechanisms involving extracellular Ado and microglia-derived soluble factors.
Persons affected with tuberous sclerosis complex (TSC) develop a wide range of neurological abnormalities including aberrant neuronal migration and seizures. In an effort to model TSC-associated central nervous system abnormalities in... more
Persons affected with tuberous sclerosis complex (TSC) develop a wide range of neurological abnormalities including aberrant neuronal migration and seizures. In an effort to model TSC-associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte-specific Tsc1 conditional knockout mice by using the Cre-LoxP system. Astrocyte-specific Tsc1-null mice exhibit electroencephalographically proven seizures after the first month of age and begin to die at 3 to 4 months. Tsc1-null mice show significant increases in astrocyte numbers throughout the brain by 3 weeks of age and abnormal neuronal organization in the hippocampus between 3 and 5 weeks. Moreover, cultured Tsc1-null astrocytes behave similar to wild-type astrocytes during log phase growth but demonstrate increased saturation density associated with reduced p27 Kip1 expression. Collectively, our results demonstrate that astrocyte-specific disruption of Tsc1 in mice provides a context-dependent growth advantage for astrocytes that results in abnormalities in neuronal organization and epilepsy.
Background: Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM... more
Background: Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Unfortunately, most patients die within 2 years of diagnosis of their disease. Molecular abnormalities vary among individual patients and also within each tumor. Indeed, one of the distinguishing features of GBM is its marked genetic heterogeneity. Due to the brain location of the tumor, the potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity.
- by Annette Bakker and +4
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- Genetics, Cell Cycle, Brain Tumor, Cell line
Aims: Glial fibrillary acidic protein (GFAP)-d i san o v e l isoform that differs in its C-terminal sequence from other GFAP isoforms. Previous studies suggest restriction of expression to the subpial layer, subventricular zone and the... more
Aims: Glial fibrillary acidic protein (GFAP)-d i san o v e l isoform that differs in its C-terminal sequence from other GFAP isoforms. Previous studies suggest restriction of expression to the subpial layer, subventricular zone and the subgranular zone astrocytes, with an absence in pathological conditions causing reactive gliosis. GFAP-d is speculated to have roles in regulation of astrocyte size and motility and a subpopulation of GFAP-d-positive glia may be multipotent stem cells. The aim of this study was to investigate its expression in common causes of lesionrelated refractory epilepsy. Methods: Hippocampal sclerosis (HS), focal cortical dysplasia (FCD) type IIB, cortical tuberous sclerosis (TSC) lesions, gangliogliomas, grey matter heterotopias and hemimegalencephaly from a wide age range of patients using both surgical and post mortem tissue specimens were studied. Results: GFAP-d expression was observed in CA4 and CA1 astrocytes in HS with less frequent labelling in the granule cell layer, even where granule cell dispersion was present. No significant labelling was noted in the subiculum in HS cases or in any subfields in non-HS epilepsy cases. Balloon cells in FCDIIB and hemimegalencephaly, giant cells in TSC and the astrocytic component of gangliogliomas showed immunoreactivity, colocalizing with conventional GFAP. No neuronal expression for GFAP-d was seen in any of the pathologies. Quantitative analysis in 10 FCDIIB and five TSC cases revealed greater numbers of GFAP-d-positive balloon cells than conventional GFAP. There was no GFAP-d expression within nodular heterotopia. Conclusions: GFAP-d expression patterns in HS overall appears to mirror regional reactive gliosis. It is a useful marker for the demonstration of balloon cells in FCD and TSC, which may be relevant to their abnormal size and localization. The lack of GFAP-d within heterotopia supports their composition from cells destined for deeper cortical layers.
Amyloid plaques appear early during Alzheimer's disease (AD), and their development is intimately linked to activated astrocytes and microglia. Astrocytes are capable of accumulating substantial amounts of neuron-derived, amyloid (1-42)... more
Amyloid plaques appear early during Alzheimer's disease (AD), and their development is intimately linked to activated astrocytes and microglia. Astrocytes are capable of accumulating substantial amounts of neuron-derived, amyloid (1-42) (A42)-positive material and other neuron-specific proteins as a consequence of their debris-clearing role in response to local neurodegeneration. Immunohistochemical analyses have suggested that astrocytes overburdened with these internalized materials can eventually undergo lysis, and radial dispersal of their cytoplasmic contents, including A42, can lead to the deposition of a persistent residue in the form of small, GFAP-rich, astrocytic amyloid plaques, first appearing in the molecular layer of the cerebral cortex. Microglia, most of which appear to be derived from blood monocytes and recruited from local blood vessels, rapidly migrate into and congregate within neuritic and dense-core plaques, but not diffuse plaques. Instead of internalizing and removing A from plaques, microglia appear to contribute to their morphological and chemical evolution by facilitating the conversion of existing soluble and oligomeric A within plaques to the fibrillar form. A fibrillogenesis may occur largely within tiny, tube-like invaginations in the surface plasma membrane of microglia. These results highlight the therapeutic potential of blocking the initial intracellular accumulation of A42 in neurons and astrocytes and inhibiting microglia-mediated assembly of fibrillar A, which is particularly resistant to degradation in Alzheimer brain.
Astrocytes are involved in multiple brain functions in physiological conditions, participating in neuronal development, synaptic activity and homeostatic control of the extracellular environment. They also actively participate in the... more
Astrocytes are involved in multiple brain functions in physiological conditions, participating in neuronal development, synaptic activity and homeostatic control of the extracellular environment. They also actively participate in the processes triggered by brain injuries, aimed at limiting and repairing brain damages. Purines may play a significant role in the pathophysiology of numerous acute and chronic disorders of the central nervous system (CNS). Astrocytes are the main source of cerebral purines. They release either adenine-based purines, e.g. adenosine and adenosine triphosphate, or guanine-based purines, e.g. guanosine and guanosine triphosphate, in physiological conditions and release even more of these purines in pathological conditions. Astrocytes express several receptor subtypes of P1 and P2 types for adenine-based purines. Receptors for guanine-based purines are being characterised. Specific ecto-enzymes such as nucleotidases, adenosine deaminase and, likely, purine nu...
Rats chronically exposed to acrylonitrile (ACN) have shown a dose-dependent increase in the incidence of astrocytomas in the brain. The mechanism(s) by which ACN induces cancer in rodents has not been established. ACN does not appear to... more
Rats chronically exposed to acrylonitrile (ACN) have shown a dose-dependent increase in the incidence of astrocytomas in the brain. The mechanism(s) by which ACN induces cancer in rodents has not been established. ACN does not appear to be directly genotoxic in the brain and thus a nongenotoxic mode of action has been proposed. Inhibition of gap junctional intercellular communication (GJIC) has been shown to be a property of many nongenotoxic carcinogens. The present study examined the effects of ACN on GJIC in a rat astrocyte transformed cell line, DI TNC1 cells (a target cell for ACN carcinogenicity) and primary cultured hepatocytes (a nontarget cell for ACN carcinogenicity). ACN inhibited GJIC in rat astrocytes in a dose-dependent manner. Inhibition of GJIC was observed following 2 h treatment with 0.10 mmol/L and 1.00 mmol/L ACN. However, in primary cultured hepatocytes, ACN exposed did not result in inhibition of GJIC even after 48 h of continued treatment. In the astrocytes, G...
Mounting evidence from in vitro experiments indicates that lactate is an efficient energy substrate for neurons and that it may significantly contribute to maintain synaptic transmission, particularly during periods of intense activity.... more
Mounting evidence from in vitro experiments indicates that lactate is an efficient energy substrate for neurons and that it may significantly contribute to maintain synaptic transmission, particularly during periods of intense activity. Since lactate does not cross the blood-brain barrier easily, blood-borne lactate cannot be a significant source. In vitro studies by several laboratories indicate that astrocytes release large amounts of lactate. In 1994, we proposed a mechanism whereby lactate could be produced by astrocytes in an activitydependent, glutamate-mediated manner. Over the last 2 years we have obtained further evidence supporting the notion that a transfer of lactate from astrocytes to neurons might indeed take place. In this article, we first review data showing the presence of mRNA encoding for two monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain. Second, by using monoclonal antibodies selectively directed against the two distinct lactate dehydrogenase isoforms, LDH 1 and LDH 5 , a specific cellular distribution between neurons and astrocytes is revealed which suggests that a population of astrocytes is a lactate 'source' while neurons may be a lactate 'sink'. Third, we provide biochemical evidence that lactate is interchangeable with glucose to support oxidative metabolism in cortical neurons. This set of data is consistent with the existence of an activity-dependent astrocyte-neuron lactate shuttle for the supply of energy substrates to neurons. OOOOOOOOOOOOOOOOOOOOOO
Remyelination of the CNS is necessary to restore neural function in a number of demyelinating conditions. Schwann cells, the myelinating cells of the periphery, are candidates for this purpose because they have more robust regenerative... more
Remyelination of the CNS is necessary to restore neural function in a number of demyelinating conditions. Schwann cells, the myelinating cells of the periphery, are candidates for this purpose because they have more robust regenerative properties than their central homologs, the oligodendrocytes. Although the ability of Schwann cells to remyelinate the CNS has been demonstrated, their capacity to enter the adult spinal cord in large numbers and effect functional recovery remains uncertain. We used cholera toxin B-subunit conjugated to saporin to demyelinate the rat lumbar spinal cord, remove macroglia, and produce paraplegia. After the removal of oligodendrocyte and astrocyte debris by invading macrophages, there was a spontaneous entry of Schwann cells into the spinal cord, along with axonal remyelination and concomitant functional recovery from paraplegia occurring within 75 d. The Schwann cells appeared to enter the dorsal funiculi via the dorsal root entry zone and the lateral f...
Purpose: Individuals with tuberous sclerosis complex (TSC) frequently have intractable epilepsy. To gain insights into mechanisms of epileptogenesis in TSC, we previously developed a mouse model of TSC with conditional inactivation of the... more
Purpose: Individuals with tuberous sclerosis complex (TSC) frequently have intractable epilepsy. To gain insights into mechanisms of epileptogenesis in TSC, we previously developed a mouse model of TSC with conditional inactivation of the Tsc1 gene in glia (Tsc1 GFAP CKO mice). These mice develop progressive seizures, suggesting that glial dysfunction may be involved in epileptogenesis in TSC. Here, we investigated the hypothesis that impairment of potassium uptake through astrocyte inward rectifier potassium (Kir) channels may contribute to epileptogenesis in Tsc1 GFAP CKO mice.
- by Michael Wong
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- Epilepsy, Hippocampus, Mice, Astrocyte
Innate immunity is a constitutive component of the central nervous system (CNS) and relies strongly on resident myeloid cells, the microglia. However, evidence is emerging that the most abundant glial cell population of the CNS, the... more
Innate immunity is a constitutive component of the central nervous system (CNS) and relies strongly on resident myeloid cells, the microglia. However, evidence is emerging that the most abundant glial cell population of the CNS, the astrocyte, participates in the local innate immune response triggered by a variety of insults. Astrocytes display an array of receptors involved in innate immunity, including Toll-like receptors, nucleotide-binding oligomerization domains, double-stranded RNAdependent protein kinase, scavenger receptors, mannose receptor and components of the complement system. Following activation, astrocytes are endowed with the ability to secrete soluble mediators, such as CXCL10, CCL2, interleukin-6 and BAFF, which have an impact on both innate and adaptive immune responses. The role of astrocytes in inflammation and tissue repair is elaborated by recent in vivo studies employing cell-type specific gene targeting.
Neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system. All forms in neuropathology therefore inevitably involve glia. The neurodegenerative diseases disrupt connectivity... more
Neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system. All forms in neuropathology therefore inevitably involve glia. The neurodegenerative diseases disrupt connectivity within brain circuits affecting neuronal-neuronal, neuronal-glial and glial-glial contacts. In addition neurodegenerative processes trigger universal and conserved glial reactions represented by astrogliosis and microglial activation. The complex of recently acquired knowledge allows us to regard the neurodegenerative diseases as primarily gliodegenerative processes, in which glial cells determine the progression and outcome of neuropathological process.
Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly... more
Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly in motor neurons in cases of ALS. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the multifunctional protein apurinic/apyrimidinic enodnuclease (APE/Ref-1). APE/Ref-1 functions as an enzyme in the DNA base-excision repair pathway and as a redox-regulation protein for transcription factors. The protein level and localization of APE/Ref-1 are changed in ALS. Immunoblotting showed that APE/Ref-1 protein levels are increased in selectively vulnerable central nervous system (CNS) regions in individuals with ALS compared to age-matched controls. Plasmid DNA repair assay demonstrated that APE from individuals with ALS is competent in repairing apurinic (AP) sites. DNA repair function in nuclear fractions is increased significantly in ALS motor cortex and spinal cord. Immunocytochemistry and single-cell densitometry revealed that APE/Ref-1 is expressed at lower levels in control motor neurons than in ALS motor neurons, which are decreased in number by 42% in motor cortex. APE/Ref-1 is increased in the nucleus of remaining upper motor neurons in ALS, which show a 38% loss of nuclear area. APE-Ref-1 is also upregulated in astrocytes in spinal cord white matter pathways in familial ALS. We conclude that mechanisms for DNA repair are activated in ALS, supporting the possibility that DNA damage is an upstream mechanism for motor neuron degeneration in this disease.
Nuclear magnetic resonance (MR) imaging provides a noninvasive method for studying the fate of transplanted cells in vivo. We studied, in animals with a cortical photochemical lesion or with a balloon-induced spinal cord compression... more
Nuclear magnetic resonance (MR) imaging provides a noninvasive method for studying the fate of transplanted cells in vivo. We studied, in animals with a cortical photochemical lesion or with a balloon-induced spinal cord compression lesion, the fate of implanted rat bone marrow stromal cells (MSCs) and mouse embryonic stem cells (ESCs) labeled with superparamagnetic iron oxide nanoparticles (Endorem). MSCs were colabeled with bromodeoxyuridine (BrdU), and ESCs were transfected with pEGFP-C1 (eGFP ESCs). Cells were either grafted intracerebrally into the contralateral hemisphere of the adult rat brain or injected intravenously. In vivo MR imaging was used to track their fate; Prussian blue staining and electron microscopy confirmed the presence of iron oxide nanoparticles inside the cells. During the first week postimplantation, grafted cells migrated to the lesion site and populated the border zone of the lesion. Less than 3% of MSCs differentiated into neurons and none into astrocytes; 5% of eGFP ESCs differentiated into neurons, whereas 70% of eGFP ESCs became astrocytes. The implanted cells were visible on MR images as a hypointense area at the injection site, in the corpus callosum and in the lesion. The hypointense signal persisted for more than 50 days. The presence of GFP-positive or BrdU-positive and nanoparticle-labeled cells was confirmed by histological staining. Our study demonstrates that both grafted MSCs and eGFP ESCs labeled with a contrast agent based on iron oxide nanoparticles migrate into the injured CNS. Iron oxide nanoparticles can therefore be used as a marker for the long-term noninvasive MR tracking of implanted stem cells.
- by Lucia Urdzíková and +1
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- Neuroscience, Psychology, Electron Microscopy, Stem Cells
The pinceau is a cerebellar structure formed by descending GABA-ergic basket cell axonal terminals converging on the initial axonal segment of Purkinje cell. Although basket cells exert a powerful inhibitory influence on the output of the... more
The pinceau is a cerebellar structure formed by descending GABA-ergic basket cell axonal terminals converging on the initial axonal segment of Purkinje cell. Although basket cells exert a powerful inhibitory influence on the output of the cerebellar cortex, the function and mode of action of the pinceau are not understood because the majority of basket cell axons fail to make identifiable synaptic contacts with the Purkinje cell axon. Several proteins were previously reported to cluster specifically in this area, including a number of voltage-activated potassium channel subunits. In this study, we used immunohistochemistry, electron microscopy, and electron tomography to examine the ultrastructural localization of a novel voltage-gated potassium channel subunit, Kv3.2, in the pinceau. We found strong, selective localization of Kv3.2 to basket cell axons. Additionally, because potassium buffering is often conducted through water channels, we studied the extent of a brain-specific water channel, aquaporin-4 (AQP4), using confocal and electron microscopy. As expected, we found AQP4 was heavily localized to astrocytic processes of the pinceau. The abundance of potassium channels and AQP4 in this area suggests rapid ionic dynamics in the pinceau, and the unusual, highly specialized morphology of this region implies that the structural features may combine with the molecular composition to regulate the microenvironment of the initial segment of the Purkinje cell axon. D 2004 Elsevier B.V. All rights reserved.
The cannabinoid CB1 and CB2 receptors, the endogenous endocannabinoid (EC) ligands anandamide (AEA) and 2-arachidonylethanolamide, and the degradative enzymes fatty acid amide hydrolase (FAAH) and monoglyceride lipase (ML) are key... more
The cannabinoid CB1 and CB2 receptors, the endogenous endocannabinoid (EC) ligands anandamide (AEA) and 2-arachidonylethanolamide, and the degradative enzymes fatty acid amide hydrolase (FAAH) and monoglyceride lipase (ML) are key elements of the EC system implicated in different physiological functions including cognition, motor activity and immune responses. Thus, both the possible neuroprotective role of ECs and their modulating action on neurotransmitter systems affected in several neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD) and multiple sclerosis (MS) are currently under investigation. Accumulating data show an unbalance in the EC system (i.e. decrease of neuronal cannabinoid CB1 receptors, increase of glial cannabinoid CB2 receptors and over-expression of FAAH in astrocytes) in experimental models of AD as well as in post-mortem brain tissue of AD patients, suggesting its possible role in inflammatory processes and in neuroprotection. However, the mechanisms of the EC modulation of immune response are not fully understood.
Neuroinflammatory processes play a significant role in the pathogenesis of Parkinson's disease (PD). Epidemiologic, animal, human, and therapeutic studies all support the presence of an neuroinflammatory cascade in disease. This is... more
Neuroinflammatory processes play a significant role in the pathogenesis of Parkinson's disease (PD). Epidemiologic, animal, human, and therapeutic studies all support the presence of an neuroinflammatory cascade in disease. This is highlighted by the neurotoxic potential of microglia . In steady state, microglia serve to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of innate and adaptive immune responses. In neurodegenerative diseases, activated microglia affect neuronal injury and death through production of glutamate, pro-inflammatory factors, reactive oxygen species, quinolinic acid amongst others and by mobilization of adaptive immune responses and cell chemotaxis leading to transendothelial migration of immunocytes across the blood-brain barrier and perpetuation of neural damage. As disease progresses, inflammatory secretions engage neighboring glial cells, including astrocytes and endothelial cells, resulting in ...
Astrocytes are the most numerous cell type within the central nervous system (CNS) and perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow. To perform these roles,... more
Astrocytes are the most numerous cell type within the central nervous system (CNS) and perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow. To perform these roles, there is a great variety of astrocytes. In this review, we summarize the function of astrocytes, in particular, their role in maintaining homeostasis at the synapse, regulating neuronal signaling, protecting neurons from oxidative damage, and determining the fate of endogenous neural precursors. The review also highlights recent developments indicating the role of astrocytes in motor neuron disease (MND), emphasizing their potential as therapeutic targets and agents in cell replacement therapy. The Cu-Zn superoxide dismutase (SOD1) gene that has been implicated in 20% of cases of familial MND must be expressed in the glial cells as well as motor neurons to produce the disease state in murine models of disease. Selectively reducing mutant SOD1 (mSOD1) in astrocytes does not affect disease onset but slows disease progression, whereas reducing mSOD1 in motor neurons delays disease onset and slows early disease but has less effect on life span. This suggests that glial cells represent potential therapeutic targets in MND. However, the lack of specific markers for astrocytes, their precursors, and sub-types means that our knowledge of astrocyte development/differentiation and response to injury lags far behind our understanding of function. Only by filling this knowledge gap can astrocytes be effectively targeted or replaced to successfully treat chronic CNS disorders such as MND. V