Molecular profile of reactive astrocytes—Implications for their role in neurologic disease

The central nervous system (CNS) can be invaded and damaged by a variety of microbes. The host response to such injury involves CNS cells, and in many cases hematogenous cells also. Recent experiments indicate that astrocytes, macroglial resident cells of the CNS, play key roles in this process. The astroglial production of trophic factors and elimination of neurotoxins are likely to fulfill important protective and reparative functions during CNS infection. In addition, astrocytes could, in concert with microglial cells, regulate the recruitment and activity of infiltrating hematogenous cells through their expression of cytokines, proteases, protease inhibitors, adhesion molecules, and extracellular matrix components. Although previous experiments suggested that astrocytes might initiate inflammatory demyelinating disease by presenting CNS antigens to autoreactive immune cells, current evidence points against such a detrimental activity. In view of the generally beneficial role of astrocytes, impairments of astroglial function by microbes or host-derived factors have the potential to contribute to neurologic disease. Diseases in which this pathogenetic process may be relevant include HIV-1-associated cognitive/motor complex and spongiform encephalopathies.

Astrocytes in infectious and immune-mediated diseases of the central nervous system.

Intracerebral inoculation of newborn and 5-week-old mice with Zika virus resulted in an early and marked enlargement of astroglial cells with patchy destruction of the pyriform cells of Ammon's horn. Replication of the virus was demonstrated in both neurones and astroglial cells. New virions appeared to be formed within networks of endoplasmic reticulum. The similarity of these ultrastructural observations to those obtained fromin vivo studies of other group B arboviruses is contrasted with the widely differing findings fromin vitro studies.

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Zika virus infection of the central nervous system of mice.

Oxidative stress and mitochondrial damage are implicated in the evolution of neurodegenerative diseases. Increased oxidative damage in specific brain regions during aging might render the brain susceptible to degeneration. Previously, we demonstrated increased oxidative damage and lowered antioxidant function in substantia nigra during aging making it vulnerable to degeneration associated with Parkinson’s disease. To understand whether aging contributes to the vulnerability of brain regions in Alzheimer’s disease, we assessed the oxidant and antioxidant markers, glutathione (GSH) metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I (CI) activity in hippocampus (HC) and frontal cortex (FC) compared with cerebellum (CB) in human brains with increasing age (0.01–80 years). We observed significant increase in protein oxidation (HC: p = 0.01; FC: p = 0.0002) and protein nitration (HC: p = 0.001; FC: p = 0.02) and increased GFAP expression (HC: p = 0.03; FC: p = 0.001) with a decreasing trend in CI activity in HC and FC compared to CB with increasing age. These changes were associated with a decrease in antioxidant enzyme activities, such as superoxide dismutase (HC: p = 0.005), catalase (HC: p = 0.02), thioredoxin reductase (FC: p = 0.04), GSH reductase (GR) (HC: p = 0.005), glutathione-s-transferase (HC: p = 0.0001; FC: p = 0.03) and GSH (HC: p = 0.01) with age. However, these parameters were relatively unaltered in CB. We suggest that the regions HC and FC are subjected to widespread oxidative stress, loss of antioxidant function and enhanced GFAP expression during aging which might make them more susceptible to deranged physiology and selective neuronal degeneration.

Elevated Oxidative Stress and Decreased Antioxidant Function in the Human Hippocampus and Frontal Cortex with Increasing Age: Implications for Neurodegeneration in Alzheimer’s Disease

Recent studies confirm that astrocytes and neurons are associated with the synaptic transmission, particularly with the regulation of glutamate (Glu) levels. Therefore, they have the capacity to modulate the Glu released from neurons into the extracellular space. It has also been demonstrated an intense astrocytic and microglia response to physical or chemical lesions of the central nervous system. However, the persistence of the response of the glial cells in adult brain had not been previously reported, after the excitotoxic damage caused by neonatal dosage of monosodium glutamate (MSG) to newborn rats. In this study, 4 mg/g body weight of MSG were administered to newborn rats at 1, 3, 5, and 7 days after birth, at the age of 60 days the astrocytes and the microglia cells were analyzed with immunohistochemical methods in the fronto-parietal cortex. Double labeling to glial fibrillary acidic protein (GFAP) and BrdU, or isolectin-B(4) and BrdU identified astrocytes or microglia cells that proliferated; immunoblotting and immunoreactivity to vimentin served for assess immaturity of astrocytic intermediate filaments. The results show that the neonatal administration of MSG-induced reactivity of astrocytes and microglia cells in the fronto-parietal cortex, which was characterized by hyperplasia; an increased number of astrocytes and microglia cells that proliferated, hypertrophy; increased complexity of the cytoplasm extension of both glial cells and expression of RNAm to vimentin, with the presence of vimentin-positive astrocytes. This glial response to neuroexcitotoxic stimulus of Glu on the immature brain, which persisted to adulthood, suggests that the neurotransmitter Glu could trigger neuro-degenerative illnesses.

Zlotnik I

Papers

The reaction of astrocytes to acute virus infections of the central nervous system.