Glia最新文献

A large wave of myelination in the central nervous system (CNS) of mammals occurs during postnatal development, coinciding with the lactation period. High prolactin (PRL) levels are present in maternal milk; however, the role of milk PRL in lactating offspring remains under-investigated. This study explores whether PRL influences myelination during postnatal development in lactating and prepubertal mice. PRL and its receptors (PRLRs) are found in white matter (WM) tracts of lactating mice, but PRL mRNA is not expressed locally, supporting that the hormone derives from maternal milk, since the pituitary gland from neonatal mice does not secrete PRL. The absence of PRLRs (in PRLR knockout [KO] mice) results in a hypomyelinated phenotype characterized by a reduced corpus callosum volume, decreased myelin staining in WM tracts (cingulum, corpus callosum and dorsal fornix), lower myelin basic protein (MBP) expression levels, and a reduced number of oligodendroglial cells, as revealed by fewer OLIG2-positive cells in PRLR-KO nursing pups at postnatal day (PD) 12. The hypomyelination observed in PRLR-KO nursing pups continues into the prepubertal stage (PD28), when locomotor alterations (reduced distance traveled and decreased velocity of movements) manifest in PRLR-KO mice. These findings show that the lack of PRL signaling leads to brain hypomyelination in neonatal mice and negatively affects locomotor function at the prepubertal stage, thereby supporting the notion that PRL is required for adequate myelination during postnatal development.

The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC-derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia-driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.

Microglia are the resident immune cells of the CNS. Under homeostatic conditions, microglia play critical roles in orchestrating synaptic pruning, debris clearance, and dead cell removal. In disease, they are powerful mediators of neuroinflammation, as they rapidly respond to injury or infection within the CNS by altering their morphology, proliferating, and releasing cytokines and other signaling molecules. Understanding the molecular pathways involved in microglial function is pivotal for advancing neurobiological research and developing effective strategies for CNS disorders. In this context, P2RY12 is a G protein-coupled receptor (GPCR) that is uniquely enriched in microglia in the parenchyma and a canonical marker of homeostatic, ramified microglia. However, P2RY12 is downregulated in activated microglia and in neurological conditions. The consequences of P2RY12 downregulation in disease-associated microglia and how they influence microglial activation remain poorly understood. In this study, we apply transcriptional and histological methods to explore the changes to microglia upon a genetic P2RY12 loss. Our findings reveal that P2RY12-deficient microglia experience alterations in distinct metabolic pathways while preserving overall homeostatic microglial transcriptional identity. Lack of P2RY12 alters signature genes involved in homeostatic iron metabolism. Importantly, the genes encoding proteins in the Glutathione Peroxidase 4 (Gpx4)-Glutathione (GSH) antioxidant pathway related to ferroptosis susceptibility are impaired upon microglial activation with lipopolysaccharide (LPS) treatment. These results highlight the critical role of P2RY12 in regulating microglial immune and metabolic transcriptional responses under both homeostatic and inflammatory conditions, providing insights into its involvement in CNS pathophysiology.

During development and following injury-induced neurogenesis, olfactory ensheathing cells (OECs) envelope the axon bundles of sensory neurons and support their growth to the glomerular destinations in the olfactory bulb. Transplantation of OECs to various neuronal injury locations showed a reparative impact; however, there was huge variability. By combining mRNA sequencing with bioinformatics analysis and immunohistochemistry, we characterized the cellular and molecular biological properties of OECs of the lamina propria and their response to neuronal injury. We found that OECs do not express NGFR (p75) under steady state conditions, questioning the common approach of isolating OECs with NGFR antibodies. While OECs express a peculiar combination of markers of different types of glial cells, they are strikingly similar to satellite glia cells of the dorsal root ganglion; for example, they showed marked upregulation of genes involved in lipid metabolism during neuronal regeneration. Similar to satellite glia cells and unlike Schwann cells, adult OECs did not proliferate in response to injury. Like endothelial cells at the blood–brain barrier and unlike other glia types, OECs showed extensive connections via the tight junction protein Claudin 5. Furthermore, OECs lack water channels, which probably explains why they sustain a stable environment after olfactory epithelium ablation. Regulation of the extracellular osmolarity seems to involve Aquaporin 1 in perineural fibroblasts together with high levels of KCNJ10, Na⁺K⁺ATPase, and gap junctions in OECs. Optimizing the clinical uses of these unique glia cells is probably made easier by this thorough characterization of marker gene expression in steady state and during neurogenesis.

Glial cells are essential for nervous system development, homeostasis, and disease response, engaging in close interactions with neurons and other glial cells to carry out their functions. A large focus of glial studies has been on investigating how these cells work with neurons to execute their supportive roles, yet glial-glial interactions are even less well understood. Our previous work established that the loss of the secreted neurotrophin, Spätzle 3 (Spz3), from Drosophila cortex glia (CG) results in the morphological degradation of CG during mid to late larval development, where they lose their intricate interactions with neurons and other glial subtypes. Building on this work, we found that the loss of CG-neuron interactions triggers aberrant infiltration and functional compensation from all neighboring glial cell types—astrocytes, ensheathing glia (EG), and subperineurial glia (SPG)—and that both the CG disruption and surrounding aberrant glial extensions are inhibited by blocking CNS growth. These aberrant glial processes are able to compensate for at least one major CG function, the clearance of apoptotic neuronal corpses via Draper-mediated engulfment. Remarkably, even as astrocytes, EG, and SPG divert their cellular resources to extend into new territories and take on new functions, they continue to maintain their normal homeostatic roles such as synaptic remodeling (astrocytes), post-injury clearance of neurite debris (ensheathing glia), and regulation of the blood–brain barrier (SPG). These findings reveal that multiple glial subtypes can dynamically respond to nearby glial dysfunction to preserve CNS homeostasis, highlighting the resilience and adaptability of glia across subtypes.

Multiple sclerosis (MS) is a chronic neurological disorder involving immune-mediated demyelination and neurodegeneration in the central nervous system (CNS). Current therapies primarily target inflammation, with limited strategies to promote remyelination or neural repair. This study explores the therapeutic potential of Brain-Derived Neurotrophic Factor (BDNF) delivered via an adeno-associated virus (AAV) vector to enhance remyelination and improve cognitive function in a subchronic cuprizone (CPZ)-induced demyelination mouse model. Sixty female C57BL/6 mice were used, with half receiving a 7-week CPZ diet to induce oligodendrocyte loss. After demyelination, mice were treated with AAV-BDNF, AAV-eGFP, or saline injections into the corpus callosum (CC), followed by a 5-week recovery phase. Behavioral assessments revealed improved cognitive performance with BDNF treatment, demonstrated by increased latency in passive avoidance tests. Immunofluorescence analysis showed increased proliferation and maturation of oligodendrocyte progenitor cells, with higher PDGFRα and CC1 markers, alongside elevated MBP. Transmission electron microscopy (TEM) indicated thicker myelin sheaths and a higher percentage of myelinated axons in AAV-BDNF-treated mice. Mitochondrial analyses revealed that BDNF treatment preserved mitochondrial integrity, with reduced swelling and improved structural regularity. Inflammatory markers showed no differences in Iba1 but indicated a trend of reduced astrocytic activation with BDNF. These results demonstrate that AAV-BDNF therapy enhances remyelination, myelin integrity, mitochondrial structure, and cognitive function in a CPZ model, underscoring its potential for treating MS. BDNF-based strategies may offer innovative avenues to improve neurological recovery and address unmet needs in MS management.

The electrogenic sodium bicarbonate transporter 1 (NBCe1/Slc4a4), predominantly expressed in astrocytes, is important for brain pH regulation and homeostasis. Increased NBCe1 expression in reactive astrocytes has been associated with neuronal degeneration in ischemic stroke. However, the effects of astrocytic NBCe1 inhibition in stroke remain contradictory, and the underlying mechanisms are unclear. Here, we show that wild-type (WT) mice exhibited elevated NBCe1 expression in the peri-lesional regions at 3 days post-stroke. Astrocytic Nbce1 gene deletion in inducible Gfap-Cre ^ERT2+/−; Nbce1 ^f/f mice (Nbce1 ^iΔAstro) resulted in a significant reduction in NBCe1 mRNA and protein expression in astrocytes. Compared to WT stroke mice, Nbce1 ^iΔAstro mice displayed reduced infarct volume, decreased brain swelling, improved cerebral blood flow, and accelerated neurological function recovery in the 1–5-day acute post-stroke period. Moreover, Nbce1 ^iΔAstro stroke mice exhibited decreased blood–brain barrier (BBB) permeability, accompanied by preserved perivascular AQP4 polarization, upregulation of Kir4.1 protein expression, and reduced astrocyte domain volume. Importantly, Nbce1 ^iΔAstro stroke brains revealed an anti-inflammatory cytokine profiling signature, marked by increased TIMP-1 expression. Together, our findings suggest that astrocytic upregulation of pH regulatory protein NBCe1 after stroke contributes to increased BBB permeability, reactive astrogliosis, inflammation, and perivascular AQP4 dysregulation. Targeting astrocytic NBCe1 may represent a promising new therapeutic strategy to mitigate astroglial dysfunction in the post-stroke brain.

In several previous studies, we have shown that macrophage targeting with the CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 led to a substantial alleviation of the neuropathy in distinct mouse models of demyelinating Charcot-Marie-Tooth (CMT) 1 forms. However, whether macrophages are also relevant drivers of the neuropathy in axonal CMT2 subtypes has not been studied so far. Here, we investigated the role of macrophages in hemizygous P0T124M mice, which develop a late-onset axonopathy accompanied by macrophage activation at 18 months of age and reflect typical pathological signs of a CMT2J neuropathy. As a tool to target macrophages before disease onset, hemizygous P0T124M mice were treated with PLX5622 from 12 to 18 months of age. Remarkably, treatment with PLX5622 not only ameliorated the peripheral neuropathy to an exceptionally high degree but also prevented distal axonal degeneration and denervation of neuromuscular junctions, leading to preserved motor function in CMT2J mice. These findings highlight macrophage-mediated inflammation as a treatment target in peripheral nerves not only in previously investigated demyelinating but also in axonal CMT neuropathies.