IF 5.1 2区医学

Glia Pub Date : 2025-10-01 Epub Date: 2025-07-09 DOI: 10.1002/glia.70056

Tingting Yang, Zhenzhou Lin, Mingjia Yu, Yongchuan Li, Jiancong Chen, Yuanchi Liu, Kaibin Huang, Suyue Pan

{"title":"SUR1-TRPM4 Regulates Aquaporin-4 Subcellular Localization by Astrocytic Endfeet Calcium Signals Following Status Epilepticus.","authors":"Tingting Yang, Zhenzhou Lin, Mingjia Yu, Yongchuan Li, Jiancong Chen, Yuanchi Liu, Kaibin Huang, Suyue Pan","doi":"10.1002/glia.70056","DOIUrl":"10.1002/glia.70056","url":null,"abstract":"Status epilepticus (SE) is a severe condition that results in uncontrollable cerebral edema and cognitive dysfunction. Recent studies suggest that the localization of aquaporin-4 (AQP4) in astrocytic endfeet plays a crucial role in regulating blood-brain water transport and cell volume control, particularly along perivascular pathways. However, the signaling mechanisms underlying AQP4 localization remain poorly understood. In this study, we utilized the genetically encoded fluorescent calcium (Ca2+) indicator GCaMp6f to investigate Ca2+ signals in astrocytic somata, processes, and endfeet during SE induction and observed enhanced Ca2+ signals in both the somata and perivascular endfeet of astrocytes. We employed genetic knockout of TRPM4 (Trpm4 -/- ) and glibenclamide treatment to explore the role of sulfonylurea receptor 1 transient receptor potential melastatin-4 (SUR1-TRPM4) channel in these Ca2+ responses. Both approaches significantly suppressed the Ca2+ signals in the astrocytic endfeet and reduced perivascular expression of the Ca2+-related signaling pathway sensor calmodulin (CaM). Furthermore, we found that AQP4 localization was no longer confined to the domains of astrocytic endfeet following SE. Inhibition of SUR1-TRPM4 through pharmacological blockade or gene deletion restored the subcellular localization of AQP4, reduced cerebral edema, and improved cognitive outcomes post-SE. Our findings suggest that SUR1-TRPM4 plays a pivotal role in regulating astrocytic Ca2+ signals and mediating the aberrant expression and subcellular localization of astrocytic AQP4 along perivascular pathways. Together, these findings demonstrate a novel molecular mechanism underscoring SUR1-TRPM4 therapy in the treatment of SE characterized by dysregulated Ca2+ signaling in astrocytic endfeet.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":"2057-2076"},"PeriodicalIF":5.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590027","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}

引用次数: 0

Astrocyte-Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in 3xTg-AD Mice. 3xTg-AD小鼠星形胶质细胞特异性Nrf2表达将神经毒性反应性星形胶质细胞转化为神经保护表型

IF 5.1 2区医学

Glia Pub Date : 2025-09-29 DOI: 10.1002/glia.70087

Shenrui Guo, Feng Wei, Hui Sun, Hongfu Jin, Weiwei Cheng, Chenglai Fu, Hui Wang, Yafu Yin

{"title":"Astrocyte-Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in 3xTg-AD Mice.","authors":"Shenrui Guo, Feng Wei, Hui Sun, Hongfu Jin, Weiwei Cheng, Chenglai Fu, Hui Wang, Yafu Yin","doi":"10.1002/glia.70087","DOIUrl":"https://doi.org/10.1002/glia.70087","url":null,"abstract":"Astrocyte reactivity is a common feature of Alzheimer's disease (AD), with reactive astrocytes traditionally subdivided into neurotoxic or neuroprotective phenotypes. It's crucial to transform neurotoxic reactive astrocytes to neuroprotective phenotypes for the treatment of AD, particularly during the progression of the disease. In this study, we evaluated the role of nuclear factor E2-related factor 2 (Nrf2) in facilitating the phenotype transformation of reactive astrocytes in vivo and in vitro by overexpressing Nrf2 in hippocampal astrocytes of 3xTg-AD mice using adeno-associated virus (AAV) vectors, as well as treating neurotoxic reactive astrocytes with dimethyl fumarate (a Nrf2 activator). We also evaluated the therapeutic effect of astrocyte-specific Nrf2 in 3xTg-AD mice with coexpression of Aβ and tau pathologies. Our findings indicate that Nrf2 could facilitate the conversion of neurotoxic reactive astrocytes to neuroprotective phenotypes in vivo and in vitro. AAV-mediated astrocyte-specific Nrf2 expression improved cognitive function, reduced Aβ and tau pathologies, rescued the loss of neurons and synapses, and ameliorated neuroinflammation in 3xTg-AD mice. These findings highlighted the role of Nrf2 in modulating reactive astrocyte phenotypes and suggested the potential for utilizing AAV to target astrocyte-specific Nrf2 as a promising therapeutic strategy for AD.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184406","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}

引用次数: 0

The Impact of Aquaporin-4 Deletion on K⁺-Induced Astrocytic Swelling Depends on K⁺ Concentration. 水通道蛋白-4缺失对K+诱导的星形细胞肿胀的影响取决于K+浓度。

IF 5.1 2区医学

Glia Pub Date : 2025-09-28 DOI: 10.1002/glia.70086

Cecilie Bugge Bakketun, Lena Catherine Roth, Daniel Marelius Bjørnstad, Ole Petter Ottersen, Vidar Jensen, Rune Enger

{"title":"The Impact of Aquaporin-4 Deletion on K+-Induced Astrocytic Swelling Depends on K+ Concentration.","authors":"Cecilie Bugge Bakketun, Lena Catherine Roth, Daniel Marelius Bjørnstad, Ole Petter Ottersen, Vidar Jensen, Rune Enger","doi":"10.1002/glia.70086","DOIUrl":"https://doi.org/10.1002/glia.70086","url":null,"abstract":"Astrocytes swell in response to elevations in extracellular K+ concentration. This K+-induced swelling is widely believed to be due to astrocytic K+ uptake, even if the underlying mechanisms are not fully understood. Conflicting results pertaining to the role of the brain water channel AQP4 in K+-induced swelling have been presented. This calls for revisiting the effect of AQP4 on K+-induced astrocytic swelling dynamics. In this study, we performed two-photon microscopy of acute hippocampal slices from wildtype (WT) and Aqp4-/- mice to assess astrocytic swelling in response to medium high 10 mM and pathologically high 50 mM [K+] solutions. We demonstrate that K+-induced swelling is attenuated in Aqp4-/- astrocytes exposed to 10 mM [K+]o compared to WT. In slices exposed to 50 mM [K+]o, peak swelling was similar between the two genotypes, whereas the cell volume recovery was more complete in Aqp4-/- astrocytes. We demonstrate that the two [K+] concentrations elicit fundamentally different astrocytic Ca2+ signaling responses, and that the Ca2+ signaling response differs between the genotypes in the 10 mM [K+]o scenario. Our findings suggest that K+-induced astrocytic swelling has different mechanistic underpinnings, depending on the K+ concentration to which the astrocytes are exposed, and that altered astrocytic Ca2+ signaling is a putative mechanism involved.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184388","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}

引用次数: 0

hiPSC-Derived Astrocytes From Individuals With Schizophrenia Induce a Dystrophic Phenotype in Microglial-Like Cells. 来自精神分裂症患者的hipsc衍生星形胶质细胞诱导小胶质样细胞的营养不良表型。

IF 5.1 2区医学

Glia Pub Date : 2025-09-19 DOI: 10.1002/glia.70085

Pablo L Cardozo, Chia-Yi Lee, Juliana P S Lacerda, Júlia S Fahel, Pablo Trindade, Gabriela Vitória, Leonardo Chicaybam, Rafaela C Cordeiro, Isaque J S de Faria, Nathália C Silva, Yaovi M H Todjro, Joana C do P Maciel, Martin H Bonamino, Luciene B Vieira, Breno F Cruz, Rodrigo Nicolato, Kristen J Brennand, Stevens K Rehen, Fabíola M Ribeiro

{"title":"hiPSC-Derived Astrocytes From Individuals With Schizophrenia Induce a Dystrophic Phenotype in Microglial-Like Cells.","authors":"Pablo L Cardozo, Chia-Yi Lee, Juliana P S Lacerda, Júlia S Fahel, Pablo Trindade, Gabriela Vitória, Leonardo Chicaybam, Rafaela C Cordeiro, Isaque J S de Faria, Nathália C Silva, Yaovi M H Todjro, Joana C do P Maciel, Martin H Bonamino, Luciene B Vieira, Breno F Cruz, Rodrigo Nicolato, Kristen J Brennand, Stevens K Rehen, Fabíola M Ribeiro","doi":"10.1002/glia.70085","DOIUrl":"https://doi.org/10.1002/glia.70085","url":null,"abstract":"Neuroinflammation, particularly astrocyte reactivity, is increasingly linked to schizophrenia (SCZ). Yet, the crosstalk between astrocytes and microglia in SCZ, especially under pro-inflammatory conditions, remains unclear. Here, we employed human induced-pluripotent stem cells to compare how astrocytes from five age-matched individuals with SCZ and five neurotypical controls, upon stimulation with TNF-α, affected microglial biology. TNF-α stimulation of SCZ astrocytes, relative to their control counterparts, triggered increased mRNA expression of pro-inflammatory cytokines and CX3CL1. Interestingly, transcriptomic and gene set enrichment analyses revealed that reactive SCZ astrocytes promoted the downregulation of biological processes associated with immune cell proliferation and activation, phagocytosis, and cell migration in induced microglial-like cells (iMGs). Under such conditions, iMGs assumed a dystrophic/senescent-like phenotype, which was associated with accelerated transcriptional aging. Functional validations showed that TNF-α-stimulated SCZ astrocytes promoted reduced synaptoneurosomes phagocytosis by iMGs. Interestingly, while both reactive control and SCZ astrocytes were capable of inducing significant microglial migration in a CX3CR1-dependent manner, TNF-α-stimulated SCZ astrocytes failed to promote greater iMG chemotaxis, compared with their stimulated control counterparts, despite secreting more than twice as much CX3CL1. This was likely due to SCZ astrocytes triggering reduction in CX3CR1 plasma membrane levels in iMGs. Altogether, these findings suggest that astrocytes contribute to SCZ pathology by altering normal microglial function and inducing a dystrophic phenotype.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084761","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}

引用次数: 0

Cover Image, Volume 73, Issue 11 封面图片，第73卷，第11期

IF 5.1 2区医学

Glia Pub Date : 2025-09-15 DOI: 10.1002/glia.24564

Binri Sasaki, Momo Oishi, Tomoka Aoki, Mai Hyodo, Chinami Onchi, Nanako Yamada, Hitomi Misawa, Momona Yamada, Chikako Hayashi, Kiyotoshi Sekiguchi, Keisuke Hamada, Yuji Yamada, Yamato Kikkawa, Motoyoshi Nomizu, Nobuharu Suzuki

引用次数: 0

Altered Inflammatory Signature in a C9ORF72-ALS iPSC-Derived Motor Neuron and Microglia Coculture Model. C9ORF72-ALS ipsc衍生的运动神经元和小胶质细胞共培养模型中炎症特征的改变

IF 5.1 2区医学

Glia Pub Date : 2025-09-15 DOI: 10.1002/glia.70084

Yujing Gao, Jessica L Brothwood, Harpreet Saini, Gregory A O'Sullivan, Carla F Bento, James M McCarthy, Nicola G Wallis, Elena Di Daniel, Brent Graham, Daniel M Tams

{"title":"Altered Inflammatory Signature in a C9ORF72-ALS iPSC-Derived Motor Neuron and Microglia Coculture Model.","authors":"Yujing Gao, Jessica L Brothwood, Harpreet Saini, Gregory A O'Sullivan, Carla F Bento, James M McCarthy, Nicola G Wallis, Elena Di Daniel, Brent Graham, Daniel M Tams","doi":"10.1002/glia.70084","DOIUrl":"https://doi.org/10.1002/glia.70084","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder involving multiple cell types in the central nervous system. The key pathological features of ALS include the degeneration of motor neurons and the initiation and propagation of neuroinflammation mediated by nonneuronal cell types such as microglia. Currently, the specific mechanisms underlying the involvement of microglia in neuroinflammation in ALS are unclear. Consequently, we generated several human-induced pluripotent stem cell (iPSC) derived motor neuron and microglia cocultures. We utilized ALS patient-derived iPSCs carrying a common genetic variant, the hexanucleotide repeat expansion (HRE) in C9ORF72, as well as C9ORF72 knockout (KO) iPSC lines. iPSC-derived motor neurons and microglia demonstrated expression of cell type-specific markers and were functional. Phenotypic assessments on motor neurons and microglia in mono- and cocultures identified dysfunction in the expression and secretion of inflammatory cytokines and chemokines in lipopolysaccharide (LPS)-stimulated C9ORF72 HRE and C9ORF72 KO microglia. Analysis of single-cell RNA sequencing data from microglia and motor neuron cocultures revealed cell type-specific transcriptomic changes. Specifically, we detected the removal of an LPS-responsive microglia subpopulation, correlating with a dampened inflammatory response in C9ORF72 HRE and C9ORF72 KO microglia. Overall, our results support the critical role of microglia-mediated neuroinflammation in ALS pathology, and our iPSC-derived models should prove a valuable platform for further mechanistic studies of ALS-associated pathways.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063063","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}

引用次数: 0

Phosphatase PP2A is Required for CNS Myelination via Proteasome-Dependent Regulation of Sox10 Expression. 磷酸酶PP2A通过蛋白酶体依赖的Sox10表达调控在中枢神经系统髓鞘形成中是必需的。

IF 5.1 2区医学

Glia Pub Date : 2025-09-11 DOI: 10.1002/glia.70082

Mengjia Liu, Yajie Zhang, Xiao-Yu Teng, Runmin Wang, Yang Liu, Jinxing Hou, He Wang, Yan-Jie Li, Zhiye Wang, Guiquan Chen

引用次数: 0

Neuronal THY1 Signaling Maintains Astrocytes in a Quiescent State. 神经元THY1信号传导维持星形细胞处于静止状态。

IF 5.1 2区医学

Glia Pub Date : 2025-09-11 DOI: 10.1002/glia.70083

Juliane Loui, Ute Krügel, Ulrike Winkler, Anja Reinert, Dorit John, Johannes Hirrlinger, Anja Saalbach

{"title":"Neuronal THY1 Signaling Maintains Astrocytes in a Quiescent State.","authors":"Juliane Loui, Ute Krügel, Ulrike Winkler, Anja Reinert, Dorit John, Johannes Hirrlinger, Anja Saalbach","doi":"10.1002/glia.70083","DOIUrl":"https://doi.org/10.1002/glia.70083","url":null,"abstract":"THY1 is a cell surface protein of mature neurons. Although the Thy1 promoter is widely used as a neuron-specific promoter for transgenic expression, the role of the endogenous THY1 protein in the brain remains largely unknown. As THY1 receptors are expressed on astrocytes, THY1 may mediate signaling between both cell types. We therefore investigated the role of THY1 signaling in neuron-astrocyte communication using a full as well as a neuron-specific Thy1-knockout mouse model. Compared to wild-type mice, aged individuals of both strains exhibited an increased expression of a subset of astrocyte activation-associated genes, such as glial fibrillary acidic protein (Gfap), vimentin (Vim), and tenascin C (Tnc), whereas others appeared unaffected. Importantly, a cortical injury caused a permanent astrocytic activation in mice with neuronal Thy1 deletion, reflected by persistent high GFAP expression. The THY1-associated modulation of gene expression was confirmed in primary astrocytes cultured with or without recombinant THY1. Moreover, functional assays indicate that THY1 inhibits astrocyte proliferation while promoting apoptosis. Interaction of neuronal THY1 with ITGB1 on astrocytes was identified to be responsible for the THY1-mediated control of astrocyte activation. These data strongly suggest that THY1-bearing neurons keep astrocytes in a quiescent state. Consequently, a depletion of THY1 supports the development of a partially activated astrocyte phenotype characterized by increased expression of intermediate filaments, increased proliferative capacity, and reduced cell death. Our findings demonstrate that neuronal THY1 is a still unrecognized novel regulator in the communication between astrocytes and neurons involved in the maintenance and restoration of tissue homeostasis in the brain.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038622","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}

引用次数: 0

Prolactin Receptor Deficiency Promotes Hypomyelination in White Matter Tracts During Postnatal Central Nervous System Maturation in Mice. 催乳素受体缺乏在小鼠出生后中枢神经系统成熟过程中促进白质束的低髓鞘化。

IF 5.1 2区医学

Glia Pub Date : 2025-09-03 DOI: 10.1002/glia.70081

Ana L Ocampo-Ruiz, José L Dena-Beltrán, Marco A Dimas-Rufino, Ximena Castillo, Dina I Vazquez-Carrillo, Andrea Silos-Guajardo, Xarubet Ruiz-Herrera, Edith Garay, Gonzalo Martínez de la Escalera, Carmen Clapp, Rogelio O Arellano, Abraham J Cisneros-Mejorado, Yazmín Macotela

{"title":"Prolactin Receptor Deficiency Promotes Hypomyelination in White Matter Tracts During Postnatal Central Nervous System Maturation in Mice.","authors":"Ana L Ocampo-Ruiz, José L Dena-Beltrán, Marco A Dimas-Rufino, Ximena Castillo, Dina I Vazquez-Carrillo, Andrea Silos-Guajardo, Xarubet Ruiz-Herrera, Edith Garay, Gonzalo Martínez de la Escalera, Carmen Clapp, Rogelio O Arellano, Abraham J Cisneros-Mejorado, Yazmín Macotela","doi":"10.1002/glia.70081","DOIUrl":"https://doi.org/10.1002/glia.70081","url":null,"abstract":"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.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991037","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}

引用次数: 0

C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk. C9orf72重复扩增诱导人ipsc衍生的小胶质细胞代谢功能障碍并调节胶质-神经元串扰。

IF 5.1 2区医学

Glia Pub Date : 2025-09-01 DOI: 10.1002/glia.70080

Marika Mearelli, Insa Hirschberg, Christin Weissleder, Carmela Giachino, María José Pérez, Malvina Dubroux, Francesca Provenzano, Mafalda Rizzuti, Linda Ottoboni, Udit Sheth, Tania F Gendron, Stefania Corti, Michela Deleidi

{"title":"C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.","authors":"Marika Mearelli, Insa Hirschberg, Christin Weissleder, Carmela Giachino, María José Pérez, Malvina Dubroux, Francesca Provenzano, Mafalda Rizzuti, Linda Ottoboni, Udit Sheth, Tania F Gendron, Stefania Corti, Michela Deleidi","doi":"10.1002/glia.70080","DOIUrl":"https://doi.org/10.1002/glia.70080","url":null,"abstract":"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.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937303","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}

引用次数: 0

Glia最新文献