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Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Liver Seq)

ABSTRACT: Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Liver Seq)

PROVIDER: PRJNA1111909 | ENA |

REPOSITORIES: ENA

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Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Liver Seq)

Project description:Microglia are resident immune cells of the central nervous system, yet their functions far exceed those related to immunology. From pruning neural synapses during development to preventing excessive neural activity throughout life, microglia are intimately involved in the brain’s most basic processes. Studies have reported a close interaction between microglia and endothelial cells, as well as both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, much less work has been done to understand microglia-endothelial cell interactions in the healthy brain. Here, we aim to determine the role of microglia at the healthy BBB. We used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism, and this effect was independent from microglial depletion, suggesting PLX5622 has off-target effects on brain vasculature.

2024-05-22 | GSE267594 | GEO

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Astro Seq)

2024-05-22 | GSE267590 | GEO

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Brain Endo Bulk Seq)

2024-05-22 | GSE267592 | GEO

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Brain Endo SC Seq)

2024-05-22 | GSE267591 | GEO

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Astro Seq)

Project description:Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Astro Seq)

| PRJNA1111904 | ENA

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Brain Endo SC Seq)

Project description:Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Brain Endo SC Seq)

| PRJNA1111903 | ENA

Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Brain Endo Bulk Seq)

Project description:Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism (Brain Endo Bulk Seq)

| PRJNA1111908 | ENA

Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

Project description:The brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states. Hypothalamus was compared between streptozotocin (STZ)-induced diabetic, ob/ob, and control mice, with 5-6 replicates per goup.

2014-10-03 | E-GEOD-62013 | biostudies-arrayexpress

Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

2014-10-03 | GSE62013 | GEO

Synergistic induction of blood-brain barrier properties

Project description:Blood–brain barrier (BBB) models derived from human stem cells are powerful tools to improve our understanding of cerebrovascular diseases and to facilitate drug development for the human brain. Yet providing stem cell–derived endothelial cells with the right signaling cues to acquire BBB characteristics while also retaining their vascular identity remains challenging. Here, we show that the simultaneous activation of cyclic AMP and Wnt/β-catenin signaling and inhibition of the TGF-β pathway in endothelial cells robustly induce BBB properties in vitro. To target this interaction, we present a small-molecule cocktail named cARLA, which synergistically enhances barrier tightness in a range of BBB models across species. Mechanistically, we reveal that the three pathways converge on Wnt/β-catenin signaling to mediate the effect of cARLA via the tight junction protein claudin-5. We demonstrate that cARLA shifts the gene expressional profile of human stem cell–derived endothelial cells toward the in vivo brain endothelial signature, with a higher glycocalyx density and efflux pump activity, lower rates of endocytosis, and a characteristic endothelial response to proinflammatory cytokines. Finally, we illustrate how cARLA can improve the predictive value of human BBB models regarding the brain penetration of drugs and targeted nanoparticles. Due to its synergistic effect, high reproducibility, and ease of use, cARLA has the potential to advance drug development for the human brain by improving BBB models across laboratories.

2024-04-18 | GSE224846 | GEO

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