Glia最新文献

Neurological diseases are associated with disruptions in the brain lipidome that are becoming central to disease pathogenesis. Traditionally perceived as static structural support in membranes, lipids are now known to be actively involved in cellular signaling, energy metabolism, and other cellular activities involving membrane curvature, fluidity, fusion or fission. Glia are critical in the development, health, and function of the brain, and glial regulation plays a major role in disease. The major pathways of glial dysregulation related to function are associated with downstream products of metabolism including lipids. Taking advantage of significant innovations and technical advancements in instrumentation, lipidomics has emerged as a popular omics discipline, serving as the prevailing approach to comprehensively define metabolic alterations associated with organismal development, damage or disease. A key technological platform for lipidomics studies is mass spectrometry (MS), as it affords large-scale profiling of complex biological samples. However, as MS-based techniques are often refined and advanced, the relative comfort level among biologists with this instrumentation has not followed suit. In this review, we aim to highlight the importance of the study of glial lipids and to provide a concise record of best practices and steps for MS-based lipidomics. Specifically, we outline procedures for glia lipidomics workflows ranging from sample collection and extraction to mass spectrometric analysis to data interpretation. To ensure these approaches are more accessible, this tutorial aims to familiarize glia biologists with sample handling and analysis techniques for MS-based lipidomics, and to guide non-experts toward generating high quality lipidomics data.

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), develop from OL precursor cells (OPCs) through a complex process involving significant morphological changes that are critically dependent on the dynamic interactions between cytoskeletal networks. Growth arrest-specific 2-like protein 1 (GAS2L1) is a cytoskeletal linker protein that mediates the cross-talk between actin filaments and microtubules. However, its role in OL and myelin development remains unknown. Here, we report that GAS2L1 is expressed in both OPCs and mature OLs, and that overexpression or knockdown of Gas2l1 in cultured OPCs in vitro impaired or enhanced their differentiation, respectively, while both inhibited their proliferation. We generated a Gas2l1^fl/fl mouse line and found that mice with conditional knockout of Gas2l1 in OL lineage cells (Olig1-Cre;Gas2l1^fl/fl, cKO) showed an increased number of mature OLs and enhanced myelination, as well as a reduction in the branching complexity of OPCs. In addition, an alternative mouse line with postnatally induced Gas2l1 ablation specifically in OPCs (Pdfgra-CreER^T2;Gas2l1^fl/fl, iKO) recapitulated the acceleration of OL and myelin development as well as the inhibition of OPC process branching. Furthermore, EdU tracking in Gas2l1 iKO mice in vivo and in their OPC cultures in vitro showed both a reduction in OPC proliferation and an increase in OL maturation. Finally, cultured OPCs from iKO mice showed an increase in filopodia extension. Taken together, our results demonstrate an effect of GAS2L1 on the regulation of OL/myelin development and may provide a novel potential therapeutic target for various diseases involving OL/myelin pathology.

Chronic stress is a major contributor to the development of major depressive disorder, one of the leading causes of disability worldwide. Using a model of repeated social defeat stress in mice, we and others have reported that neuroinflammation plays a dynamic role in the development of behavioral deficits consistent with social avoidance and impaired reward responses. Animals susceptible to the model also exhibit hypomyelination in the medial prefrontal cortex, indicative of changes in the differentiation pathway of cells of the oligodendroglial lineage (OLN). We computationally confirmed the presence of immune oligodendrocytes, a population of OLN cells, which express immune markers and myelination deficits. In the current study, we report that microglia are necessary to induce expression of antigen presentation markers (and other immune markers) on oligodendroglia. We further associate the appearance of these markers with changes in the OLN and confirm that microglial changes precede OLN changes. Using co-cultures of microglia and OLN, we show that under inflammatory conditions the processes of phagocytosis and expression of MHCII are linked, suggesting potential priming for antigen presentation by OLN cells. Our findings provide insights into the nature of these OLN cells with immune capabilities, their obligatory interaction with microglia, and identify them as a potential cellular contributor to the pathological manifestations of psychosocial stress.

A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

Multiple sclerosis (MS) is the most prevalent human inflammatory disease of the central nervous system with demyelination and glial scar formation as pathological hallmarks. Glial cells are key drivers of lesion progression in MS with roles in both tissue damage and repair depending on the surrounding microenvironment and the functional state of the individual glial subtype. In this review, we describe recent developments in the context of glial cell diversity in MS summarizing key findings with respect to pathological and maladaptive functions related to disease-associated glial subtypes. A particular focus is on the spatial and temporal dynamics of glial cells including subtypes of microglia, oligodendrocytes, and astrocytes. We contextualize recent high-dimensional findings suggesting that glial cells dynamically change with respect to epigenomic, transcriptomic, and metabolic features across the inflamed rim and during the progression of MS lesions. In summary, detailed knowledge of spatially restricted glial subtype functions is critical for a better understanding of MS pathology and its pathogenesis as well as the development of novel MS therapies targeting specific glial cell types.

Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of intractable epilepsy. FCDs are classified into different subtypes including FCD IIa and IIb, characterized by a blurred gray-white matter boundary or a transmantle sign indicating abnormal white matter myelination. Recently, we have shown that myelination is also compromised in the gray matter of FCD IIa of the temporal lobe. Since myelination is key for brain function, which is imbalanced in epilepsy, in the current study, we investigated myelination in the gray matter of FCD IIa and IIb from the frontal lobe on the morphological, ultrastructural, and transcriptional level. We found that FCD IIa presents with an ordinary radial myelin fiber pattern, but with a reduced thickness of myelin sheaths of 500-1000 nm thick axons in comparison to FCD IIb and with an attenuation of the myelin synthesis machinery. In contrast, FCD IIb showed an irregular and disorganized myelination pattern covering an enlarged area in comparison to FCD IIa and controls and with increased numbers of myelinating oligodendrocytes (OLs). FCD IIb had significantly thicker myelin sheaths of large caliber axons (above 1000 nm) when compared to FCD IIa. Accordingly, FCD IIb showed a significant up-regulation of myelin-associated mRNAs in comparison to FCD IIa and enhanced binding capacities of the transcription factor MYRF to target sites in myelin-associated genes. These data indicate that FCD IIa and IIb are characterized by a differential dysregulation of myelination in the gray matter of the frontal lobe.

Cover Illustration: 3D IMARIS render of Airyscan confocal z stack image showing the GFP microglia (green) processes diving into the diffuse amyloid plaque shell stained with anti-Aβ antibody D54D2 (red). Activated microglia interacts here with the plaque in two ways: with soma going deep into the plaque, and with thin processes which are intertwined in looser amyloid layers. (See Gotkiewicz, M., et al, https://doi.org/10.1002/glia.24628)

Cover Illustration: 3D IMARIS render of Airyscan confocal z stack image showing the GFP microglia (green) processes diving into the diffuse amyloid plaque shell stained with anti-Aβ antibody D54D2 (red). Activated microglia interacts here with the plaque in two ways: with soma going deep into the plaque, and with thin processes which are intertwined in looser amyloid layers. (See Gotkiewicz, M., et al, https://doi.org/10.1002/glia.24628)

A subpopulation of astrocytes expressing WD Repeat Domain 49 (WDR49) was recently identified in frontotemporal lobar degeneration (FTLD) with GRN pathogenic variants. This is the first study to investigate their expression and relation to pathology in other FTLD subtypes and Alzheimer's disease (AD). In a postmortem cohort of TDP-43 proteinopathies (12 GRN, 11 C9orf72, 9 sporadic TDP-43), tauopathies (13 MAPT, 8 sporadic tau), 10 AD, and four controls, immunohistochemistry and immunofluorescence were performed for WDR49 and pathological inclusions on frontal, temporal, and occipital cortical sections. WDR49-positive cell counts (adjusted per mm²) were examined and related to digitally quantified percentage areas of TDP-43/tau pathology and semiquantitative scores of neurodegeneration. Quantitative colocalization analysis of WDR49 and pathological inclusions was done. WDR49-positive astrocytes were present across FTLD subtypes and AD in the brain parenchyma and (peri-)vascular space, with distinct morphological patterns, and were particularly enriched in gray matter. In controls, sporadic WDR49-positive cells were found enveloping vessels. WDR49-positive astrocytes were most abundant in the frontal cortex (FC) of GRN cases and temporal cortex in GRN, AD, and sporadic primary tauopathy. In the occipital cortex, only a few cells were found across groups. WDR49-positive astrocyte counts positively correlated with the severity of neurodegeneration and TDP-43 pathology but not tauopathy. Furthermore, in frontotemporal cortices, WDR49 partly colocalized with TDP-43 (14%-21%) and tau (31%-45%). In conclusion, WDR49 is a marker for a subset of astrocytes with different morphologies across FTLD and AD, reflecting the severity of neurodegeneration. These astrocytes may become activated in neurodegeneration in response to pathological damage and migrate from the vessel wall to the parenchyma.