Astrocyte dysfunction in neurological disorders: a molecular perspective.
ABSTRACT Recent work on glial cell physiology has revealed that glial cells, and astrocytes in particular, are much more actively involved in brain information processing than previously thought. This finding has stimulated the view that the active brain should no longer be regarded solely as a network of neuronal contacts, but instead as a circuit of integrated, interactive neurons and glial cells. Consequently, glial cells could also have as yet unexpected roles in the diseased brain. An improved understanding of astrocyte biology and heterogeneity and the involvement of these cells in pathogenesis offers the potential for developing novel strategies to treat neurological disorders.
- SourceAvailable from: Thomas Zeis[Show abstract] [Hide abstract]
ABSTRACT: Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients. Copyright © 2015. Published by Elsevier Inc.Brain Behavior and Immunity 04/2015; 88. DOI:10.1016/j.bbi.2015.04.013 · 6.13 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-β1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-β pathway. TGF-β1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-β1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-β1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-β1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. GLIA 2014Glia 12/2014; 62(12). DOI:10.1002/glia.22713 · 6.03 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Amyloid-beta (Aβ) deposition plays a crucial role in the progression of Alzheimer's disease (AD). The Aβ deposited extracellularly can be phagocytosed and degraded by surrounding activated astrocytes, but the precise mechanisms underlying Aβ clearance mediated by astrocytes remain unclear. In this study, we performed tandem mass tag-based quantitative proteomic analysis on the cerebral cortices of 5-month-old APP/PS1 double-transgenic mice. Among the 2668 proteins quantified, 35 proteins were upregulated and 12 were downregulated, with most of these proteins being shown here for the first time to be differently expressed in the APP/PS1 mouse. The altered proteins were involved in molecular transport, lipid metabolism, autophagy, inflammation, and oxidative stress. One specific protein, PEA15 (phosphoprotein enriched in astrocytes 15kDa) upregulated in APP/PS1 mice, was verified to play a critical role in astrocyte-mediated Aβ phagocytosis. Furthermore, PEA15 levels were determined to increase with age in APP/PS1 mice, indicating that Aβ stimulated the upregulation of PEA15 in the APP/PS1 mouse. These results highlight the function of PEA15 in astrocyte-mediated Aβ phagocytosis, and thus provide novel insight into the molecular mechanism underlying Aβ clearance. The protein-expression profile revealed here should offer new clues to understand the pathogenesis of AD and potential therapeutic targets for AD.Journal of Proteomics 08/2014; 110. DOI:10.1016/j.jprot.2014.07.028 · 3.93 Impact Factor