Glia最新文献

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.

The activity of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OLs) throughout life drives myelination, which is crucial for rapid neuronal communication. OLs in the aging brain demonstrate a reduced capacity for myelin formation and maintenance, but the underlying differentiation of individual OLs and morphological changes of their myelin in aging remain unclear. Here, we utilized Pdgfra-CreER ^T2 :Tau-mGFP double transgenic mice to selectively label and visualize newly generated OLs in aged (78-week-old) mice and compared them with those in young (8-week-old) mice. We revealed a significantly lower percentage of newly generated OLs that differentiated into mature OLs and a decreased rate of myelinating OLs accumulation in aged mice compared with young mice. Additionally, newly generated myelinating mature OLs in aged mice demonstrated significantly greater height compared with those in young mice. Furthermore, myelin internodes were significantly shorter and significantly fewer in aged mice compared with young mice. Our results indicate age-related impairments in the differentiation efficiency of aged OPCs and age-related morphological changes in OLs. These alterations in newly generated OLs may contribute to impaired myelination, reduced myelin turnover, and disrupted myelin maintenance in aged mice.

Cover Illustration: Oligodendrocyte binds to laminin on the perivascular basement membrane in the murine cortex at the age of postnatal day 16 (red: CC-1; green: laminin alpha-2; blue: DAPI). (See Sasaki, B., et al, https://doi.org/10.1002/glia.70027)

Glial fibrillary acidic protein (GFAP) is a type-3 intermediate filament protein mainly expressed in astrocytes in the central nervous system. Mutations in GFAP cause Alexander disease (AxD), a rare and fatal neurological disorder. How exactly mutant GFAP eventually leads to white and gray matter deterioration in AxD remains unknown. GFAP is known to be expressed also in neural precursor cells in the developing brain. Here, we used AxD patient-derived induced pluripotent stem cells (iPSCs) to explore the impact of mutant GFAP during neurodifferentiation. Our results show that GFAP is already expressed in iPSCs. Moreover, we have found that mutations in GFAP can severely affect neural organoid development through altering lineage commitment in embryoid bodies. Together, these results support the notion that GFAP plays a role as an early modulator of neurodevelopment.

Schwann cells are the glial cells in the peripheral nervous system responsible for the production of myelin, which is essential for rapid, saltatory conduction in nerves. However, it has become increasingly recognized that Schwann cells are also key regulators of neuron viability and function, especially for sensory neurons. Neurons and Schwann cells form a tightknit, interdependent couple with complex mechanisms of communication that are only beginning to be understood. There is growing evidence that Schwann cell metabolism profoundly influences axons through the release of a variety of metabolites. These glial cells serve as energy depots for axon function, supplying lactate and/or pyruvate during repeated firing and after injury. Lipid metabolism in Schwann cells, which is critical for myelin production, also affects axon viability, such that disruptions in the production or breakdown of lipids can lead to axon dysfunction and subsequent degeneration. Here, we discuss emerging concepts on the mechanisms by which Schwann cell metabolites influence neuron activity and survival, with particular focus on how dysfunction of lipid metabolism can lead to axon degeneration and the development of peripheral neuropathy.