Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders

Keyser, Jacques De; Mostert, Jop; Koch, Marcus

doi:10.1016/j.jns.2007.08.044

Cited by 204 publications

(132 citation statements)

References 141 publications

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“…Yet, it is clear both microglia and astrocytes are capable of expressing many proinflammatory effectors, like Tnf, Il1a, Il1b, Ccl6, Cxcl1, and Cxcl10, when similarly stimulated with the appropriate TLR agonists (63) or when glia are analyzed ex vivo from Alzheimer's mice (67). Other cell types in the brain, including neurons, oligodendrocytes, and endothelial cells, have all been shown to produce and respond to cytokines and chemokines (68)(69)(70), and these cells may also contribute to the alterations in transcription observed in prion disease. Furthermore, macrophages are recruited to the brain during scrapie infection (47) and likely contribute to the chronic inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Carroll

Striebel

Race

et al. 2015

J Virol

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Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre-and postclinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1␣, phosphorylated-STAT1␣ (pSTAT1␣), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL-1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo. However, in IL1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed. IMPORTANCEPrion infection leads to PrPres deposition, gliosis, and neuroinflammation in the central nervous system before signs of clinical illness. Using a scrapie mouse model of prion disease to assess various time points postinoculation, we identified 15 unreported genes that were increased in the brains of scrapie-infected mice and were associated with inflammation and/or JAK-STAT activation. Comparison of mice infected with two scrapie strains (22L and RML), which have dissimilar neuropathologies, indicated that the inflammatory responses and gene expression profiles in the brains were similar. Genes that increased prior to clinical signs might be involved in controlling scrapie infection or in facilitating damage to host tissues. We tested the possible role of the endogenous IL-1Ra, which was increased at 70 days p.i. In scrapie-infected mice deficient in or overexpressing IL-1Ra, there was no observable effect on gliosis, PrPres formation, disease tempo, pathology, or expression of inflammatory genes analyzed. P rion diseases are infectious progressive neurodegenerative disorders that can affect both h...

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Section: Discussionmentioning

confidence: 99%

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Carroll

Striebel

Race

et al. 2015

J Virol

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“…Recently, there has been growing interest in the glial cells, as they may play a key role in the epileptogenic process. Long-term investigations have failed to determine whether the enhanced activation of astrocytes is a favorable phenomenon, or whether it enhances neuronal changes in various pathological conditions [1,2]. The cells in question play numerous neuroprotective roles: they maintain ion homeostasis and appropriate concentration of neurotransmitters in the extracellular space.…”

Section: Investigations Of Hippocampal Astrocytes In Investigations Omentioning

confidence: 99%

Investigations of hippocampal astrocytes in lipopolysaccharide-preconditioned rats in the pilocarpine model of epilepsy

Jaworska-Adamu¹,

Dmowska²,

Cybulska³

et al. 2011

Folia Histochem Cytobiol.

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Abstract: Abstract: Abstract: The present paper is the first work to determine the effect of lipopolysaccharide (LPS) in the pilocarpine model of epilepsy on the morphology of rat hippocampal astrocytes in vivo. The study involved adult male Wistar rats, which 72 hours prior to administration of pilocarpine hydrochloride (PILO) were intraperitoneally (ip) preconditioned with LPS at a dose of 0.5 mg/kg b.w. The control animals were administered (ip) saline or LPS alone. The astrocytes in the control animals displayed characteristic stellate morphology. Examinations of the astrocytes were performed on days one, three and 21 of the pilocarpine model of epilepsy (i.e. in the acute, silent and chronic periods). The astrocytes of the CA1 and CA3 pyramidal layers of the hippocampus were observed and analyzed at the structural and ultrastructural levels. It was demonstrated that on days one and three, glial cells from both the nonpreconditioned and the LPS-preconditioned animals displayed similar reactive changes, manifesting themselves as swelling of cell bodies, glial processes, and astrocytosis. Moreover, reduction in cell organelles aggregated at one pole and the presence of vacuoles were observed. The most pronounced astrogliosis and cell swelling occurred on day 21. We conclude that LPS has no effect on the morphology of astrocytes in the pilocarpine model of epilepsy, unlike the results obtained by other authors in vitro.

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“…Impaired or deranged interplay among neurons and glia may shift the balance from normal brain physiology to neurodegeneration (De Keyser et al 2008;Sofroniew 2009). Nevertheless, the precise role of microglia and/or astrocytes in neurodegenerative mechanisms has not yet been clearly defined.…”

Section: Introductionmentioning

confidence: 99%

The neuron-astrocyte-microglia triad in CA3 after chronic cerebral hypoperfusion in the rat: Protective effect of dipyridamole

Lana

Ugolini

Melani

et al. 2017

Experimental Gerontology

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Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders

Cited by 204 publications

References 141 publications

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

Investigations of hippocampal astrocytes in lipopolysaccharide-preconditioned rats in the pilocarpine model of epilepsy

The neuron-astrocyte-microglia triad in CA3 after chronic cerebral hypoperfusion in the rat: Protective effect of dipyridamole

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