Glia最新文献

{"title":"WDR49-Positive Astrocytes Mark Severity of Neurodegeneration in Frontotemporal Lobar Degeneration and Alzheimer's Disease","authors":"Ana Rajicic,&nbsp;Lucia A. A. Giannini,&nbsp;Emma Gerrits,&nbsp;Renee van Buuren,&nbsp;Shamiram Melhem,&nbsp;Johan A. Slotman,&nbsp;Annemieke J. M. Rozemuller,&nbsp;Bart J. L. Eggen,&nbsp;John C. van Swieten,&nbsp;Harro Seelaar","doi":"10.1002/glia.24663","DOIUrl":"10.1002/glia.24663","url":null,"abstract":"<p>A subpopulation of astrocytes expressing WD Repeat Domain 49 (WDR49) was recently identified in frontotemporal lobar degeneration (FTLD) with <i>GRN</i> 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 <i>postmortem</i> cohort of TDP-43 proteinopathies (12 <i>GRN</i>, 11 <i>C9orf72</i>, 9 sporadic TDP-43), tauopathies (13 <i>MAPT</i>, 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 <i>GRN</i> cases and temporal cortex in <i>GRN</i>, 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.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 5","pages":"948-968"},"PeriodicalIF":5.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Axonal Selectivity of Myelination by Single Oligodendrocytes Established During Development in Mouse Cerebellar White Matter","authors":"Batpurev Battulga,&nbsp;Yasuyuki Osanai,&nbsp;Reiji Yamazaki,&nbsp;Yoshiaki Shinohara,&nbsp;Nobuhiko Ohno","doi":"10.1002/glia.24660","DOIUrl":"10.1002/glia.24660","url":null,"abstract":"<p>Myelin formation by oligodendrocytes regulates the conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits where the axons are involved, it remains unclear if oligodendrocytes selectively form myelin sheaths around specific subtypes of axons. Using the combination of rabies virus-mediated single oligodendrocyte labeling and immunostaining with tissue clearing, we revealed that approximately half of the oligodendrocytes preferentially myelinate axons originating from Purkinje cells in the white matter of adult mouse cerebella. The preference for Purkinje cell axons was more pronounced during development when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated Purkinje cell axons. Preferential myelination of Purkinje cell axons was further confirmed by immuno-electron microscopy and transgenic mice that label early-born oligodendrocytes. Transgenic mice that label oligodendrocytes differentiated at the early development showed that early-born oligodendrocytes preferentially myelinate Purkinje cell axons in the matured cerebellar white matter. In contrast, transgenic mice that label oligodendrocytes differentiated after the peak of cerebellar myelination showed that the later-differentiated oligodendrocytes dominantly myelinated non-Purkinje cell axons. These results demonstrate that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination by individual oligodendrocytes is established depending on the timing of their differentiation during development. Our data provide the evidence that there is a critical time window of myelination that a specific subtype of axons are dominantly myelinated by the oligodendrocytes.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"873-886"},"PeriodicalIF":5.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipids: Emerging Players of Microglial Biology","authors":"Priya Prakash,&nbsp;Caitlin E. Randolph,&nbsp;Katherine A. Walker,&nbsp;Gaurav Chopra","doi":"10.1002/glia.24654","DOIUrl":"10.1002/glia.24654","url":null,"abstract":"<p>Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration. Moreover, cholesterol is essential not only for microglial survival but, along with other lipids such as fatty acids, is crucial for the formation, function, and accumulation of lipid droplets, which modulate microglial activity in inflammatory diseases. Other lipids, including acylcarnitines and ceramides, participate in various signaling pathways within microglia. Despite the complexity of the microglial lipidome, only a few studies have investigated the effects of specific lipid classes on microglial biology. In this review, we focus on major lipid classes and their roles in modulating microglial function. We also discuss novel analytical techniques for characterizing the microglial lipidome and highlight gaps in current knowledge, suggesting new directions for future research on microglial lipid biology.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 3","pages":"657-677"},"PeriodicalIF":5.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro-Inflammatory Stimuli","authors":"Peter Lund Ovesen,&nbsp;Kristian Juul-Madsen,&nbsp;Narasimha S. Telugu,&nbsp;Vanessa Schmidt,&nbsp;Silke Frahm,&nbsp;Helena Radbruch,&nbsp;Emma Louise Louth,&nbsp;Anders Rosendal Korshøj,&nbsp;Frank L. Heppner,&nbsp;Sebastian Diecke,&nbsp;Helmut Kettenmann,&nbsp;Thomas E. Willnow","doi":"10.1002/glia.24659","DOIUrl":"10.1002/glia.24659","url":null,"abstract":"<p>Sorting protein-related receptor containing class A repeats (SORLA) is an intracellular trafficking receptor encoded by the Alzheimer's disease (AD) gene <i>SORL1</i> (<i>sortilin-related receptor 1</i>). Recent findings argue that altered expression in microglia may underlie the genome-wide risk of AD seen with some <i>SORL1</i> gene variants, however, the functional significance of the receptor in microglia remains poorly explained. Using unbiased omics and targeted functional analyses in iPSC-based human microglia, we identified a crucial role for SORLA in sensitizing microglia to pro-inflammatory stimuli. We show that SORLA acts as a sorting factor for the pattern recognition receptor CD14, directing CD14 exposure on the cell surface and priming microglia to stimulation by pro-inflammatory factors. Loss of SORLA in gene-targeted microglia impairs proper CD14 sorting and blunts pro-inflammatory responses. Our studies indicate an important role for SORLA in shaping the inflammatory brain milieu, a biological process important to local immune responses in AD.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"857-872"},"PeriodicalIF":5.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24659","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi Layered Omics Approaches Reveal Glia Specific Alterations in Alzheimer's Disease: A Systematic Review and Future Prospects","authors":"Özkan İş,&nbsp;Yuhao Min,&nbsp;Xue Wang,&nbsp;Stephanie R. Oatman,&nbsp;Ann Abraham Daniel,&nbsp;Nilüfer Ertekin-Taner","doi":"10.1002/glia.24652","DOIUrl":"10.1002/glia.24652","url":null,"abstract":"<p>Alzheimer's disease (AD) is the most common neurodegenerative dementia with multi-layered complexity in its molecular etiology. Multiple omics-based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi-omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD-associated molecular perturbations in brain glial cells. The findings from over 200 AD-related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 3","pages":"539-573"},"PeriodicalIF":5.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice","authors":"Hidenori Aizawa,&nbsp;Miho Matsumata,&nbsp;Laura Ayaka Noguera Oishi,&nbsp;Fumie Nishimura,&nbsp;Deepa Kamath Kasaragod,&nbsp;Xintong Yao,&nbsp;Wanqin Tan,&nbsp;Tomomi Aida,&nbsp;Kohichi Tanaka","doi":"10.1002/glia.24647","DOIUrl":"10.1002/glia.24647","url":null,"abstract":"<p>The habenula has been implicated in psychiatric disorders such as depression, primarily because of its role in the modulation of the dopaminergic and serotonergic systems, which play a role in the pathophysiology of these disorders. Despite growing evidence supporting the role of the habenula in behavioral regulation, the process by which neural cells develop in the habenula remains elusive. Since the habenular anlage is found in the prosomere 2 domain expressing transcription factor Dbx1 in mouse embryos, we hypothesized that the Dbx1-expressing prosomere domain is a source of astrocytes that modulate neuronal activity in the habenula. To address this, we examined the cell lineage generated from Dbx1-expressing cells in male mice using tamoxifen-inducible Cre recombinase under the control of the Dbx1 promoter. Perinatal induction of Cre activity labeled cells migrating radially from the ventricular zone to the pial side of the habenular anlage, and eventually showed astrocyte-like morphology with expression of the marker protein, S100β, for mature astrocytes in the habenula of the adult mouse. Photostimulation of astrocytes expressing ChR2 released potassium ions into the extracellular space, which in turn excited the neurons with an increased firing rate in the lateral habenula. Finally, photostimulation of habenular astrocytes exacerbated depression-like phenotypes with reduced locomotor activity, exaggerated despair behavior and impaired sucrose preference in open-field, tail suspension and sucrose preference tests, respectively. These results indicated that the Dbx1-expressing perinatal domain generated astrocytes that modulated neuronal activity via the regulation of extracellular potassium levels.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"759-772"},"PeriodicalIF":5.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24647","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Potential of Growth Hormone in Peripheral Nerve Injury: Enhancing Schwann Cell Proliferation and Migration Through IGF-1R-AKT and ERK Signaling Pathways","authors":"Jiaqian Chen,&nbsp;Tingcheng Zhang,&nbsp;Chaohu Wang,&nbsp;Peirong Niu,&nbsp;Liehao Huang,&nbsp;Rongrong Guo,&nbsp;Chengdong Wu,&nbsp;Huarong Zhang,&nbsp;Zhiyong Wu,&nbsp;Songtao Qi,&nbsp;Yi Liu","doi":"10.1002/glia.24653","DOIUrl":"10.1002/glia.24653","url":null,"abstract":"<div>\u0000 \u0000 <p>Peripheral nerve injury (PNI) represents a prevalent condition characterized by the demyelination of affected nerves. The challenge of remyelinating these nerves and achieving satisfactory functional recovery has long been a persistent issue. The specific contributions of growth hormone (GH) in the aftermath of PNI have remained ambiguous. Our investigations have demonstrated that GH not only enhances neurological function scores but also promotes remyelination within a three-week period. Further in vivo studies corroborated that GH facilitates nerve function improvement by mitigating neuronal apoptosis. In vitro, the ideal concentration of GH for exerting effects on Schwann cells (SCs) has been identified as 80 ng/mL. Subsequent research uncovered GH's profound impact on SCs proliferation, cell cycle progression, and migration. Through RNA sequencing and additional experiments, it was discovered that GH treatment elevates the phosphorylation levels of IGF-1R, AKT, and ERK. Moreover, the GH-induced proliferation and migration of SCs were significantly diminished by the inhibition of the IGF-1R pathway, achieved through pre-treatment with Linsitinib. The outcomes of this investigation suggest that GH can significantly enhance the proliferation and migration of SCs, presenting it as a viable option for PNI repair.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"805-821"},"PeriodicalIF":5.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single Cell Deletion of the Transcription Factors Trps1 and Sox9 in Astrocytes Reveals Novel Functions in the Adult Cerebral Cortex","authors":"Poornemaa Natarajan,&nbsp;Christina Koupourtidou,&nbsp;Thibault de Resseguier,&nbsp;Manja Thorwirth,&nbsp;Riccardo Bocchi,&nbsp;Judith Fischer-Sternjak,&nbsp;Sarah Gleiss,&nbsp;Diana Rodrigues,&nbsp;Michael H. Myoga,&nbsp;Jovica Ninkovic,&nbsp;Giacomo Masserdotti,&nbsp;Magdalena Götz","doi":"10.1002/glia.24645","DOIUrl":"10.1002/glia.24645","url":null,"abstract":"<p>Astrocytes play key roles in brain function, but how these are orchestrated by transcription factors (TFs) in the adult brain and aligned with astrocyte heterogeneity is largely unknown. Here we examined the localization and function of the novel astrocyte TF Trps1 (Transcriptional Repressor GATA Binding 1) and the well-known astrocyte TF Sox9 by Cas9-mediated deletion using Mokola-pseudotyped lentiviral delivery into the adult cerebral cortex. Trps1 and Sox9 levels showed heterogeneity among adult cortical astrocytes, which prompted us to explore the effects of deleting either Sox9 or Trps1 alone or simultaneously at the single-cell (by patch-based single-cell transcriptomics) and tissue levels (by spatial transcriptomics). This revealed TF-specific functions in astrocytes, such as synapse maintenance with the strongest effects on synapse number achieved by Trps1 deletion and a common effect on immune response. In addition, spatial transcriptomics showed non-cell-autonomous effects on the surrounding cells, such as oligodendrocytes and other immune cells with TF-specific differences on the type of immune cells: Trps1 deletion affecting monocytes specifically, while Sox9 deletion acting mostly on microglia and deletion of both TF affecting mostly B cells. Taken together, this study reveals novel roles of Trps1 and Sox9 in adult astrocytes and their communication with other glial and immune cells.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"737-758"},"PeriodicalIF":5.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of OPC Mitochondrial Function by Inhibiting USP30 Promotes Their Differentiation","authors":"Allison L. Soung,&nbsp;Roxanne V. Kyauk,&nbsp;Shristi Pandey,&nbsp;Yun-An A. Shen,&nbsp;Mike Reichelt,&nbsp;Han Lin,&nbsp;Zhiyu Jiang,&nbsp;Praveen Kirshnamoorthy,&nbsp;Oded Foreman,&nbsp;Benjamin E. Lauffer,&nbsp;Tracy J. Yuen","doi":"10.1002/glia.24648","DOIUrl":"10.1002/glia.24648","url":null,"abstract":"<p>Multiple lines of evidence indicate that mitochondrial dysfunction occurs in demyelinating diseases, such as multiple sclerosis (MS). Failure of remyelination is thought to be caused in part by a block of oligodendrocyte progenitor cell (OPC) differentiation into oligodendrocytes, which generate myelin sheaths around axons. The process of OPC differentiation requires a substantial amount of energy and high demand for ATP which is supplied through the mitochondria. In this study, we highlight mitochondrial gene expression changes during OPC differentiation in two murine models of remyelination and in human postmortem MS brains. Given these transcriptional alterations, we then investigate whether genetic alteration of USP30, a mitochondrial deubiquitinase, enhances OPC differentiation and myelination. By genetic knockout of USP30, we observe increased OPC differentiation and myelination without affecting OPC proliferation and survival in in vitro and ex vivo assays. We also find that OPC differentiation is accelerated in vivo following focal demyelination in USP30 knockout mice. The promotion of OPC differentiation and myelination observed is associated with increased oxygen consumption rates in USP30 knockout OPCs. Together, these data indicate a role for mitochondrial function and USP30 in OPC differentiation and myelination.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 4","pages":"773-787"},"PeriodicalIF":5.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unboxing “Omics” in Glial Biology to Understand Neurological Disease","authors":"Jonathan R. Weinstein,&nbsp;Suman Jayadev,&nbsp;Shane Liddelow,&nbsp;B. J. L. Eggen","doi":"10.1002/glia.24651","DOIUrl":"10.1002/glia.24651","url":null,"abstract":"","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 3","pages":"448-450"},"PeriodicalIF":5.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}