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Activity-dependent cholesterol biosynthesis in human-derived astrocytes regulates the functional maturation of human-derived cortical neurons

ABSTRACT: Activity-dependent cholesterol biosynthesis in human-derived astrocytes regulates the functional maturation of human-derived cortical neurons

PROVIDER: PRJNA990748 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25118300_1.fastq.gz	Fastqsanger.gz
	SRR25118300_2.fastq.gz	Fastqsanger.gz
	SRR25118301_1.fastq.gz	Fastqsanger.gz
	SRR25118301_2.fastq.gz	Fastqsanger.gz
	SRR25118302_1.fastq.gz	Fastqsanger.gz

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Activity-dependent cholesterol biosynthesis in human-derived astrocytes regulates the functional maturation of human-derived cortical neurons

Project description:Astrocytes regulate the functional maturation of neurons by providing trophic support, regulating membrane properties and coordinating synapse formation. However, it is unclear to what degree astrocytes use activity-dependent mechanisms in these intercellular signalling processes. Using an induced pluripotent stem cell system and long-term optogenetic stimulation of human astrocytes, we reveal that activity-dependent astrocytic signals enhance the functional maturation of human cortical neurons, through increases in synaptic connectivity and excitability. Transcriptomic analyses determine that this involves the activity-dependent up-regulation of cholesterol synthesis – a process ascribed to astrocytes, which regulates neuronal maturation. Up-regulated astrocyte genes encode enzymes and transcription factors that control the levels of cholesterol synthesis. Biochemical assays confirm an activity-dependent upregulation of cholesterol synthesis in astrocytes, which is required for the maturational effects upon neurons. Thus, we reveal a novel mechanism that may dynamically match astrocyte function to neuronal needs, and identify targets for modulating cholesterol synthesis in the CNS.

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ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

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2023-09-12 | PXD045298 | Pride

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Project description:The impact of Apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cell models, post-mortem brain and APOE targeted replacement mice. Population and isogenic models uncover that APOE4 local haplotype rather than a single risk allele alone contributes to the risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 leads to elevated de novo cholesterol synthesis despite the intracellular cholesterol accumulation due to lysosomal sequestration of cholesterol in astrocytes. Transcriptome analyses uncovered Matrisome dysregulation associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes, co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

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Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [mouseApoe]

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Project description:Palmitic Acid Upregulates Type I Interferon-Mediated Antiviral Response and Cholesterol Biosynthesis in Human Astrocytes

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Palmitic Acid Upregulates Type I Interferon-Mediated Antiviral Response and Cholesterol Biosynthesis in Human Astrocytes

Project description:Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid abundant in the diet that at high concentrations may penetrate the blood brain barrier and stimulate the production of pro-inflammatory cytokines, leading to inflammation in astrocytes. The use of the synthetic neurosteroid tibolone in protection against fatty acid toxicity is emerging, but its transcriptional effects on palmitic acid induced lipotoxicity remain unclear. Herein, we performed a transcriptome profiling of normal human astrocytes to investigate the molecular mechanisms by which palmitic acid causes cellular damage to astrocytes, and whether tibolone could reverse its detrimental effects. Astrocytes undergo a profound transcriptional change at 2 mM palmitic acid, affecting the expression of 739 genes, 366 upregulated and 373 downregulated. However, tibolone at 10 nM does not entirely reverse palmitic acid effects. Additionally, the protein protein interaction reveals two novel gene clustering modules. The first module involves astrocyte defense responses by upregulation of pathways associated with antiviral innate immunity, and the second is linked to lipid metabolism. Our data suggest that activation of viral response signaling pathways might be so far, the initial molecular mechanism of astrocytes in response to a lipotoxic insult by palmitic acid, triggered particularly upon increased expression levels of *IFIT2*, *IRF1*, and *XAF1*. Therefore, this novel approach using a global gene expression analysis may shed light on the pleiotropic effects of palmitic acid on astrocytes, and provide a basis for future studies addressed to elucidate these responses in neurodegenerative conditions, which is highly valuable for the design of therapeutic strategies.

2021-02-10 | GSE166500 | GEO

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