Glia最新文献

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. However, the surrounding glia, including oligodendrocytes, also exhibit ALS pathology and TDP-43 related dysfunction. Given that oligodendrocytes, the myelinating cells of the central nervous system, are essential for motor neuron function, they may play an underappreciated role in ALS. Here, we have extensively characterized the oligodendrocyte lineage and myelin integrity in the TDP-43^Q331K mouse model of ALS. In the lumbar spinal cord of end-stage male TDP-43^Q331K mice (TDP-43), compared to wild-type littermates (WT), oligodendrocyte precursor cell (OPC) density, oligodendrocyte proliferation, and differentiation were all increased. There was no correlative increase in the density of mature oligodendrocytes, which was determined to be due to an increase in oligodendroglial apoptosis. In end-stage mice, myelin reflectance was increased in the dorsal column of TDP-43 mice, while electron microscopy showed myelin damage and misfolding in the TDP-43 mice. Our data suggest that the oligodendrocyte lineage is impacted in TDP-43 related ALS.

Inflammation, and particularly microglial cells, has become a central feature in Parkinson's disease (PD) pathology. The transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable nonselective channel involved in the pathological mechanism of several inflammatory and neurodegenerative diseases. However, the role of TRPM2 in inflammation and microglial activation in the context of PD remains unclear. Here, we combined both in vivo and in vitro PD models to investigate that question. Male and female TRPM2 partial and complete knockout mice were submitted to the 6-hydroxidopamine mouse model of PD. We assessed microglia and lysosome-associated protein (CD68) density levels, microglial morphology and cluster classification, CD68 area in individual microglial cells, and the protein levels of six different cytokines in the substantia nigra pars compacta and the striatum. Our results indicate that TRPM2 deletion reduced microglial density, rescued its morphology, decreased CD68 staining area within microglia, and lowered pro-inflammatory cytokines levels in both male and female mice. To better understand TRPM2 involvement in PD pathology, we selectively knocked-down TRPM2 in neurons, microglia, or both cells in a human neuron-microglia co-culture PD model. An improvement in cell viability and a decrease in cell death were observed across the different experimental approaches. Lastly, TRPM2 deletion revealed reduced microglial phagocytosis and decreased expression of inflammation-related molecules. For the first time, we demonstrated that TRPM2 is a critical mediator of microglial function in the context of PD. Thus, this study suggests that TRPM2 inhibition may offer a novel therapeutic target for PD modification.

Depression, a prevalent mental health disorder, is multifaceted in its etiology. Growing evidence suggests that dysregulation of heat shock protein 60 (HSP60) contributes to neurological dysfunction, but its role in astrocyte-mediated depressive-like behaviors and neuroinflammation remains poorly understood. Here, we sought to investigate whether astrocyte-specific HSP60 depletion disrupts cellular homeostasis and is associated with astrocyte dysfunction that contributes to depressive-like behaviors and related inflammatory signaling, with a particular emphasis on the role of autophagy. Employing animal models, we demonstrate that chronic stress could dysregulate HSP60 in the brain of mice concurrent with inducing depressive-like symptoms in mice. Furthermore, astrocyte-specific HSP60 depletion (HSP60 cKO) male mice exhibited depressive-like behaviors, alongside significant disruption in astrocyte morphology and impaired autophagic processes within the cortex. Remarkably, these deleterious effects of HSP60 depletion were mitigated by triggering autophagy via urolithin A (UA) treatment, both in the brains of HSP60 cKO mice and in primary astrocytes derived from these mice. These findings shed light on the intricate interplay between astrocytes, HSP60, and autophagy in the etiology of depression, offering potential avenues for therapeutic strategies aimed at modulating astrocytic function and autophagic pathways to alleviate depressive symptoms and astrocyte-associated neuroinflammation.

Olfactory Ensheathing Cells (OECs) are glial cells originating from the neural crest and are critical for bundling olfactory axons to the brain. Their development is crucial for the migration of Gonadotropin-Releasing Hormone-1 (GnRH-1) neurons, which are essential for puberty and fertility. OECs have garnered interest as potential therapeutic targets for central nervous system lesions, although their development is not fully understood. Our single-cell RNA sequencing of mouse embryonic nasal tissues suggests that OECs and Schwann cells share a common origin from Schwann cell precursors yet exhibit significant genetic differences. The transcription factors Yap and Taz have previously been shown to play a crucial role in Schwann cell development. We used Sox10-Cre mice to conditionally ablate Yap and Taz in the migrating neural crest and its derivatives. Our analyses showed reduced Sox10+ glial cells along nerves in the nasal region, altered gene expression in Schwann cells (SCs), melanocytes, and OECs, and a significant reduction in olfactory sensory neurons and vascularization in the vomeronasal organ. However, despite these changes, GnRH-1 neuronal migration remained unaffected. Our findings highlight the importance of the Hippo pathway in OEC development and how changes in cranial neural crest derivatives indirectly impact the development of olfactory epithelia.

Astrocytes provide physical and metabolic support for neurons, regulate the blood-brain barrier, and react to injury, infection, and disease. When astrocytes become reactive, maintenance of the inflammatory state and its functional implications throughout chronic neuroinflammation are all poorly understood. Several models of acute inflammation have revealed astrocyte subpopulations that go beyond a two-activation state model, instead encompassing distinct functional subsets. However, how reactive astrocyte (RA) subsets evolve over time during chronic inflammatory disease or infection has been difficult to address. Here we use a prolific human pathogen, Toxoplasma gondii, that causes lifelong infection in the brain alongside a Lcn2CreERT2 reporter mouse line to examine reactive astrocyte subsets during chronic neuroinflammation. Single-cell RNA sequencing revealed diverse astrocyte populations including transcriptionally unique Lcn2CreERT2+ RAs which change over the course of infection in a subset-dependent manner. In addition to an immune-regulating Lcn2CreERT2+ astrocyte population enriched with gene transcripts encoding chemokines CCL5, CXCL9, CXCL10, and receptors CCR7 and IL7R, a specific subset of Lcn2CreERT2+ astrocytes highly expressed transthyretin (Ttr), a secreted carrier protein involved in glycolytic enzyme activation and potential vasculature regulation and angiogenesis. These findings provide novel information about the evolution and diversity of reactive astrocyte subtypes and functional signatures at different stages of infection, revealing an undocumented role for transthyretin-expressing astrocytes in immune regulation at the central nervous system (CNS) vasculature.

Trifluoperazine (TFP), a known inhibitor of Ca²⁺-bound calmodulin (Ca²⁺/CaM), has been reported to elevate cytosolic Ca²⁺ levels by disinhibiting inositol 1,4,5-triphosphate receptor 2 (IP₃R2), thereby suppressing glioblastoma invasion and inducing apoptosis. Interestingly, TFP induces a sustained Ca²⁺ plateau, sensitive to extracellular Ca²⁺, suggesting involvement of Ca²⁺ entry such as store-operated calcium entry (SOCE). However, the underlying molecular mechanism remains elusive. Here, we report that TFP induces sustained Ca²⁺ signals by blocking the Ca²⁺/CaM-dependent desensitization of SOCE channels in cortical astrocyte cultures. TFP induces a prolonged Ca²⁺ response, with distinct kinetics compared to other Ca²⁺ modulators such as TFLLR-NH₂ (a G_αq-coupled GPCR agonist) and thapsigargin (a sacro/endoplasmic reticulum Ca²⁺-ATPase inhibitor). Under extracellular Ca²⁺-free conditions, Ca²⁺ levels increase without reaching a plateau, suggesting that the sustained Ca²⁺ signal relies on Ca²⁺ influx. Pharmacological analysis shows that sustained Ca²⁺ signals by TFP are CaM-dependent. Gene silencing targeting STIM1 and Orai1-3 confirmed their essential roles in the sustained response. We find that TFP effectively "locks open" SOCE channels by inhibiting their desensitization, maintaining SOCE activity. This effect is also observed in ex vivo hippocampal dentate gyrus astrocytes. Structural modeling supports a mechanism in which TFP disrupts the interaction between Ca²⁺/CaM and the SOAR domain of STIM1. Together, these findings indicate that TFP elevates cytosolic Ca²⁺ levels by maintaining SOCE activation, offering novel insights into the molecular actions of this drug. TFP can be a pharmacological tool for SOCE research as it locks SOCE channels open.

Oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS) are capable of proliferating, migrating, and differentiating into oligodendrocytes. OPCs are crucial for the myelination of axons during development and remyelination after injury in adulthood. OPCs also play important roles in promoting angiogenesis, neurotrophy, and immunomodulation, which makes them a relevant element of regenerative approaches for many CNS diseases, especially demyelinating ones. OPC migration is important during neurodevelopment and regeneration, and as such is regulated by a multitude of intracellular and extracellular factors. Identifying these factors will facilitate the optimized regulation of OPC migration and thus enhance therapeutic effects. This field is a current research hotspot, and new findings are constantly emerging. Here, we comprehensively review research progress on the regulatory factors that control OPC migration.

A greater understanding of the neurobiology of nicotine is needed to reduce or prevent chronic addiction, ameliorate detrimental nicotine withdrawal effects, and improve cessation rates. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), α4β2 and α7. Protein kinase B-β (Pkb-β or Akt2) expression is restricted to astrocytes in mice and humans and is activated by nicotine. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specific Akt2 conditional knockout (cKO) and full Akt2 KO mice. For in/ex vivo studies, we examined mice exposed to chronic nicotine for 2 weeks in drinking water (200 μg/mL) or following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 h. Our in vitro studies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereas Akt2 cKO mice showed enhanced acute responses and reduced area following chronic exposure. In culture, we found 100 μM nicotine sufficient for morphological changes and blocking α7 or α4β2 nAChRs prevented observed morphological changes. We performed conditioned place preference (CPP) in Akt2 cKO mice, which revealed reduced nicotine preference in cKO mice compared to controls. Finally, we performed RNASeq comparing nicotine- and LPS-mediated gene expression, identifying robust differences between these two astrocytic stimuli. These findings show the importance of nAChRs and AKT2 signaling in the astrocytic response to nicotine.

Multiple sclerosis (MS) is the most common non-infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmune disease, MS is driven by the immune system's attack on CNS myelin, resulting in cumulative disability. However, conventional anti-inflammatory treatments often fail to prevent progressive deterioration, particularly in the absence of overt inflammation, highlighting the need for a deeper understanding of its pathogenesis. Recent research has revealed a more complex disease mechanism involving both peripheral immune responses and intrinsic CNS factors, with glial cells playing a central role. Persistent inflammation in MS is associated with mixed active/inactive lesions dominated by microglia and astrocyte dysregulation. These glial populations exhibit maladaptive activation, contributing to failed remyelination and ongoing neurodegeneration. Transcriptomic and epigenomic alterations as well as aging further exacerbate glial dysfunction, creating a self-perpetuating cycle of inflammation and damage. Emerging evidence suggests that the interplay between peripheral immune cells and glial populations and the potential dual-use nature of molecular tools shared by the immune system and CNS disrupts homeostatic signaling, leading to a loss of tissue integrity. This review synthesizes findings on glial cell biology in MS, with a focus on microglia and astrocytes, while addressing their roles in demyelination, synapse loss, and neurodegeneration. The limitations of animal models, particularly EAE, in replicating the complexity of MS are also addressed. Finally, critical questions are outlined to guide future research into glial pathology and to identify novel therapeutic approaches targeting progressive MS.