RNA-seq profiling of astrocytes after microglial ablation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE142022 | GEO | 2020/09/22
REPOSITORIES: GEO
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Project description:RNA-seq profiling of astrocytes after microglial ablation
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Project description:Chronic high-fat feeding triggers widespread metabolic dysfunction including obesity, insulin resistance, and diabetes. While these ultimate pathological states are relatively well understood, we have a limited understanding of how high-fat intake first triggers physiological changes. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on spatial and learning memory. Acute high-fat intake increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation, fission and metabolic skewing towards aerobic glycolysis. These effects are generalized, detectable in the hypothalamus, hippocampus, and cortex all within 1-3 days of HFD exposure. In vivo microglial ablation and conditional DRP1 deletion experiments show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglial cells as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons instead as alternate bioenergetic and protective substrates. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.
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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
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Project description:The only validated treatment to prevent brain damage associated with hypoxia-ischemia (HI) encephalopathy of the newborn is controlled hypothermia with limited benefits. Additional putative neuroprotective drug candidates include sildenafil citrate, a phosphodiesterase-type 5 inhibitor. The main objective of this preclinical study is to assess its ability to reduce HI-induced neuroinflammation, in particular through its potential effect on microglial activation. HI was induced in P10 Sprague–Dawley rats by unilateral carotid permanent artery occlusion and hypoxia (HI), and treated by either hypothermia (HT) alone, Sildenafil (Sild) alone or combined treatment (SildHT). Lesion size, glial activation were analyzed by immunohistochemistry, qRT-PCR and proteomic analyses performed at P13. Exposure to any treatment was not associated with significant reduction in lesions size both in cerebral cortex and hippocampus, 72h after HI. Significant reductions in either Iba1+ (within the ipsilateral hemisphere) or GFAP+ cells (within the ipsilateral hippocampus) were observed in SildHT group, but not in the other treatment groups. In microglia sorted cells, pro-inflammatory markers, ie. Il1b, Il6, Nos2, and CD86 were significantly downregulated in SildHT treatment group only. These changes were restricted to ipsilateral hemisphere, were not evidenced in sorted astrocytes, and were not sex-dependent. Proteomic analyses in sorted microglia refined the pro-inflammatory effect of HI and confirmed a biologically relevant impact of SildHT on specific molecular pathways including notably genes related to neutrophilic functions. Our findings demonstrate that Sildenafil combined with controlled hypothermia confers maximum effect to mitigate microglial activation induced by HI through complex proteomic regulation. The reduction of neuroinflammation induced by Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.
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