Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene and characterized by profound impairments in neuronal maturation and synaptic connectivity. Increasing evidence indicates that astrocyte dysfunction contributes to RTT pathogenesis through non-cell-autonomous mechanisms, although the molecular pathways underlying defective astrocyte-neuron communication are only partially understood. Astrocytes are the primary source of cholesterol in the brain and support neuronal maturation and synaptic function by supplying cholesterol through ApoE-containing lipoproteins. Although alterations in brain cholesterol metabolism have been reported in RTT, the underlying cellular mechanisms and their functional consequences remain poorly investigated. Here, we studied cholesterol homeostasis in Mecp2 knock-out (KO) astrocytes and its impact on neuron-astrocyte communication. Mecp2 KO astrocytes exhibited reduced nuclear localization of the transcriptional regulator Srebp2, together with the downregulation of genes involved in cholesterol biosynthesis and transport. These molecular alterations were associated with intracellular cholesterol and desmosterol accumulation, reduced Abca1 expression and defective ApoE lipidation, despite preserved ApoE expression and cholesterol secretion. Importantly, similar alterations were detected in acutely isolated astrocytes and in the cerebral cortex of Mecp2 deficient mice, demonstrating that impaired cholesterol homeostasis extends beyond in vitro models. Functionally, cholesterol supplementation of astrocyte-conditioned medium rescued the synaptic defects induced in wild-type neurons by Mecp2 KO astrocytes. Moreover, cholesterol treatment restored pre- and post-synaptic density, as well as axon initial segment length in Mecp2 heterozygous (HET) neurons. Together, these findings identify defective astrocyte-to- neuron cholesterol trafficking as a key mechanism contributing to neuronal dysfunction in RTT and suggest that strategies aimed at restoring cholesterol functional availability might represent a promising therapeutic avenue for RTT.
Neuroinflammation often disrupts cerebral cholesterol homeostasis and leads to white matter damage and demyelination. However, the molecular mechanisms underlying these defects have remained enigmatic. In this study, we report that inflammation is associated with aberrant activation of Wnt signaling in astrocytes. While Wnt signaling increases astrocytic expression of SREBF2 protein and intracellular cholesterol level, it simultaneously inhibits the expression of APOE and reduces cholesterol efflux from astrocytes. The extracellular cholesterol supply is essential for the activation of the expression of MYRF transcription factor and myelin-associated genes in oligodendrocytes. Moreover, the defective oligodendrocyte differentiation and myelin gene expression caused by astrocytic Wnt activation in transgenic mice can partially be rescued by chemical-enhanced ApoE expression. Our findings suggest a regulatory pathway of "inflammation → Wnt signaling → cholesterol metabolism → myelin integrity" and provide important insights into the molecular mechanisms underlying inflammation-induced demyelinating diseases and future therapeutic strategies.
Jian-Nan Zhang, Jia-Ru Zheng, Yi Ai et al.· Cell Reports· 0 citations
Cortico-striatal synaptic dysfunction is an early hallmark of Huntington's disease (HD), yet the mechanisms underlying synapse loss and its reversibility remain poorly understood. Brain cholesterol is essential for neuronal and synaptic function, and dysregulated cholesterol metabolism has emerged as a key feature of HD, with reduced cholesterol biosynthesis reported in rodent models and cholesterol replenishment shown to be beneficial. Consistent with these findings, GWAS identified HD modifier loci outside canonical DNA repair pathways, including MED15, which among its functions supports SREBF2-mediated transcription of cholesterol biosynthesis genes, and a chr22 locus encompassing SREBF2, the master regulator of cholesterol biosynthesis. These findings suggest that pathways regulating cholesterol homeostasis may contribute to modifying the course of HD. Here, we show that increasing cholesterol availability prevents synapse loss and restores cortico-striatal connectivity in HD models. Cholesterol supplementation restores excitatory synapse density in vivo and in vitro. In primary HD neurons, cholesterol stabilizes dendritic spines and promotes the enrichment of GluA1-containing AMPA receptors in mature mushroom spines during chemically induced long-term potentiation, consistent with improved synaptic plasticity. Using microfluidic devices to spatially resolve the cortico-striatal circuit, we identified a compartment-specific mechanism whereby cholesterol delivery to cortical neurons is necessary and sufficient to restore cortico-striatal connectivity, whereas cholesterol administration to the striatal compartment selectively restores intra-striatal inhibitory synapses. Mechanistically, NMDA receptor and BDNF/TrkB signalling mediate the cholesterol-dependent restoration of synaptic connectivity, establishing cholesterol as a critical regulator of cortico-striatal synaptic integrity in HD and supporting targeting cholesterol homeostasis as a therapeutic strategy to restore synaptic function.
Allegra Lenci, Michela Villa, Andrea Scolz et al.· Pharmacological Research· 0 citations
It is demonstrated that Egfr knockout during the critical period of neuronal maturation results in a transient absence of astrocytes, with recovery observed in adult mice, and developmental disruption of EGFR signaling leads to transient astrocyte loss and impaired astrocyte–neuron crosstalk.
Xin Jiang, Yanqing Qi, Lin Yang et al.· Nature Communications· 0 citations
Multiple sclerosis (MS) is characterized by inflammatory demyelination, oxidative stress, and neurological dysfunction. Despite disease-modifying therapies, chronic active lesions and ongoing neurodegeneration remain largely untreated, highlighting the need for mechanistically informed translational targets.
We analyzed a human single-nucleus RNA-sequencing dataset (GSE279180) including healthy controls and MS samples. Astrocyte subpopulations were examined using reclustering, pseudotime inference, co-expression network analysis, SLC7A11-high/low stratification, virtual knockout prediction, and gene set enrichment analysis. Key findings were further assessed in vivo using a cuprizone-induced demyelination mouse model.
Broad cellular remodeling was observed in MS lesions, including altered neuroactive ligand-receptor interactions, calcium signaling, glutamatergic synapse, and synaptic vesicle cycle-related pathways. SLC7A11 was enriched in astrocytes and increased along later pseudotime stages. SLC7A11-high astrocytes were linked to impaired antioxidant defense (GSH/GPX4) and synaptic vesicle-related remodeling. CPZ-treated mice showed decreased SLC7A11/GPX4 colocalization and increased SYP–GFAP colocalization, along with behavioral deficits, demyelination, and inflammatory-redox imbalance.
SLC7A11-associated astrocyte states are associated with redox imbalance and synaptic microenvironment remodeling in MS. These states may inform future biomarker development and therapeutic investigation. Our findings provide a glial-state framework linking neuroinflammation, oxidative stress, and synaptic dysfunction, highlighting potential avenues for translational strategies in MS.
Jian Liu, Jun-Jun Yin, Meng Pu et al.· Journal of Translational Med...· 0 citations
Astrocytes are one of the most abundant types of glial cells in the central nervous system (CNS) and play pivotal roles in metabolic support, synaptic regulation, and neurotransmitter homeostasis. Astrocytic dysfunction is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), and lipid metabolism constitutes a central axis for maintaining astrocyte function and CNS homeostasis. Here, we provide a systematic review of recent advances in astrocyte lipid metabolism, summarizing the fundamental roles of astrocytes in the CNS and focusing on the biosynthesis, degradation, and trafficking mechanisms of fatty acids, cholesterol, and the tightly linked organelles known as lipid droplets. We further analyze the relationships and potential pathogenic mechanisms linking lipid metabolic disturbances, such as impaired fatty acid β-oxidation, cholesterol accumulation, and dysregulated lipid droplet dynamics, to neurodegeneration. The review also presents current frameworks for classifying reactive astrocytes, including the classical A1/A2 paradigm and more recently identified subtypes, and examines how lipid metabolic processes influence phenotype transitions. Finally, we propose a regulatory axis: lipid metabolism dysregulation leads to cellular phenotype conversion, which in turn drives disease progression, to emphasize the central role of lipid metabolism in astrocyte reactivity and neuropathology. This synthesis fills a gap in the literature at the interface of lipid metabolism and astrocyte functional regulation, and it offers a conceptual framework and candidate targets to guide future investigation into metabolic mechanisms of neurodegeneration and the development of precision therapeutic strategies.
