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Temporal Profiling of Male Cortical Astrocyte Transcription Predicts Molecular Shifts From Early Development to Aging.

IF 5.4 2区医学

Glia Pub Date : 2025-03-13 DOI: 10.1002/glia.70010

Xiaoran Wei, Jiangtao Li, Michelle L Olsen

{"title":"Temporal Profiling of Male Cortical Astrocyte Transcription Predicts Molecular Shifts From Early Development to Aging.","authors":"Xiaoran Wei, Jiangtao Li, Michelle L Olsen","doi":"10.1002/glia.70010","DOIUrl":"https://doi.org/10.1002/glia.70010","url":null,"abstract":"Astrocytes are the most abundant glial cell type in the central nervous system (CNS). Astrocytes are born during the early postnatal period in the rodent brain and mature alongside neurons, demonstrating remarkable morphological structural complexity, which is attained in the second postnatal month. Throughout this period of development and across the remainder of the lifespan, astrocytes participate in CNS homeostasis, support neuronal partners, and contribute to nearly all aspects of CNS function. In the present study, we analyzed astrocyte gene expression in the cortex of wild-type male rodents throughout their lifespan (postnatal 7 days to 18 months). A pairwise timepoint comparison of differential gene expression during early development and CNS maturation (7-60 days) revealed four unique astrocyte gene clusters, each with hundreds of genes, which demonstrate unique temporal profiles. These clusters are distinctively related to cell division, cell morphology, cellular communication, and vascular structure and regulation. A similar analysis across adulthood and in the aging brain (3 to 18 months) identified similar patterns of grouped gene expression related to cell metabolism and cell structure. Additionally, our analysis identified that during the aging process astrocytes demonstrate a bias toward shorter transcripts, with loss of longer genes related to synapse development and a significant increase in shorter transcripts related to immune regulation and the response to DNA damage. Our study highlights the critical role that astrocytes play in maintaining CNS function throughout life and reveals molecular shifts that occur during development and aging in the cortex of male mice.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613044","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

Unexpected Remyelination in the Absence of Matrix Metalloproteinase 7.

IF 5.4 2区医学

Glia Pub Date : 2025-03-10 DOI: 10.1002/glia.70005

Rianne P Gorter, Andrea J Arreguin, Wendy Oost, Jenny C de Jonge, Harm H Kampinga, Sandra Amor, Holly Colognato, Wia Baron

{"title":"Unexpected Remyelination in the Absence of Matrix Metalloproteinase 7.","authors":"Rianne P Gorter, Andrea J Arreguin, Wendy Oost, Jenny C de Jonge, Harm H Kampinga, Sandra Amor, Holly Colognato, Wia Baron","doi":"10.1002/glia.70005","DOIUrl":"https://doi.org/10.1002/glia.70005","url":null,"abstract":"In multiple sclerosis (MS), an influx of immune cells into the central nervous system leads to focal demyelinating lesions in the brain, optic nerve, and spinal cord. As MS progresses, remyelination increasingly fails, leaving neuronal axons vulnerable to degeneration and resulting in permanent neurological disability. In chronic MS lesions, the aberrant accumulation of extracellular matrix (ECM) molecules, including fibronectin and hyaluronan, impairs oligodendrocyte progenitor cell differentiation, contributing to remyelination failure. Removing inhibitory ECM is therefore a therapeutic target to stimulate remyelination in MS. Intriguingly, the expression of the fibronectin-degrading enzyme matrix metalloproteinase 7 (MMP7) is decreased in chronic MS lesions compared to control white matter. Therefore, we examined the role of MMP7 upon cuprizone-induced demyelination, hypothesizing that the lack of MMP7 would lead to impaired breakdown of its ECM substrates, including fibronectin, and diminished remyelination. Unexpectedly, remyelination proceeded efficiently in the absence of MMP7. In the remyelination phase, the lack of MMP7 did not lead to the accumulation of fibronectin or of laminin, another MMP7 substrate. Moreover, in the setting of chronic demyelination, levels of fibronectin were actually lower in MMP7-/- mice, while levels of hyaluronan, which is not a known MMP7 substrate, were also lower. Overall, these results indicate that MMP7 is not essential for remyelination in the cuprizone model and point to an unexpected complexity in how MMP7 deficiency influences fibronectin and hyaluronan levels in chronic demyelination.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583880","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

Neuroinflammation: An Oligodendrocentric View.

IF 5.4 2区医学

Glia Pub Date : 2025-03-10 DOI: 10.1002/glia.70007

Lindsay K Festa, Kelly L Jordan-Sciutto, Judith B Grinspan

引用次数: 0

The INO80 Chromatin Remodeling Complex Regulates Histone H2A.Z Mobility and the G1-S Transition in Oligodendrocyte Precursors.

IF 5.4 2区医学

Glia Pub Date : 2025-02-28 DOI: 10.1002/glia.70006

Jordan L Wright, Yi Jiang, Stuart G Nayar, Huiliang Li, William D Richardson

引用次数: 0

Astrocyte-Specific Phenotyping of FAD^4T as an Alzheimer's Disease Mouse Model.

IF 5.4 2区医学

Glia Pub Date : 2025-02-26 DOI: 10.1002/glia.70002

Ki Jung Kim, Jae-Hun Lee, Jiwoon Lim, Taehee Lee, Jinhyeong Joo, Mridula Bhalla, Tao Wang, Rui Feng, C Justin Lee

{"title":"Astrocyte-Specific Phenotyping of FAD4T as an Alzheimer's Disease Mouse Model.","authors":"Ki Jung Kim, Jae-Hun Lee, Jiwoon Lim, Taehee Lee, Jinhyeong Joo, Mridula Bhalla, Tao Wang, Rui Feng, C Justin Lee","doi":"10.1002/glia.70002","DOIUrl":"https://doi.org/10.1002/glia.70002","url":null,"abstract":"Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, characterized by memory decline and behavioral changes. Its pathological features include senile plaques, neurofibrillary tangles, and reactive gliosis, comprising abnormal accumulations of β-amyloid peptide (Aβ) and hyperphosphorylated tau protein surrounded by reactive astrocytes and microglia. Recently, it has emerged that severe reactive astrocytes and MAOB-dependent production of GABA and H2O2 are the real causes of learning and memory impairment and neurodegeneration. Diverse mouse models for AD have been developed to clarify pathological mechanisms and discover therapeutic strategies and drugs. However, there are many shortfalls and discrepancies among them. A new AD mouse model named FAD4T has been developed to overcome various shortcomings. Here, we employed astrocyte-focused screening procedures to examine the pathological features of FAD4T as an AD model. Our results revealed that the FAD4T mice showed abnormal accumulation of Aβ plaques in overall brain regions at 6 and 12 months. We found astrocytic hypertrophy with a significant elevation of GFAP and LCN2. However, the expressions of MAOB and iNOS, a severe reactive astrocyte marker, were unchanged. Electrophysiological and behavioral analysis indicated aberrant tonic GABA release, reduced neuronal activity, and impaired CA1-specific memory. These findings demonstrate that FAD4T mice mimic pathological and functional features of AD, different from other AD mouse models. These findings demonstrate that FAD4T mimics some features of AD patients but lacks other important features, such as severe reactive astrocytes and neurodegeneration. This astrocyte-focused screening method offers valuable tools for advancing AD research and developing new therapeutic strategies.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497635","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

Generation of an Inducible Destabilized-Domain Cre Mouse Line to Target Disease Associated Microglia.

IF 5.4 2区医学

Glia Pub Date : 2025-02-23 DOI: 10.1002/glia.70004

Caden M Henningfield, Minh Ngo, Kaitlin M Murray, Nellie E Kwang, Kate I Tsourmas, Jonathan Neumann, Zachary A Pashkutz, Shimako Kawauchi, Vivek Swarup, Thomas E Lane, Grant R MacGregor, Kim N Green

{"title":"Generation of an Inducible Destabilized-Domain Cre Mouse Line to Target Disease Associated Microglia.","authors":"Caden M Henningfield, Minh Ngo, Kaitlin M Murray, Nellie E Kwang, Kate I Tsourmas, Jonathan Neumann, Zachary A Pashkutz, Shimako Kawauchi, Vivek Swarup, Thomas E Lane, Grant R MacGregor, Kim N Green","doi":"10.1002/glia.70004","DOIUrl":"10.1002/glia.70004","url":null,"abstract":"The function of microglia during progression of Alzheimer's disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed mouse lines that express either Cre recombinase (Cre) for constitutive targeting, or destabilized-domain Cre recombinase (DD-Cre) for inducible targeting from the Cst7 locus (Cst7DD-Cre) to specifically manipulate disease associated microglia (DAM) and crossed with Ai14 tdTomato cre-reporter line mice. Cst7Cre was found to target all brain resident myeloid cells, due to transient developmental expression of Cst7, but no expression was found in the inducible Cst7DD-Cre mice. Further crossing of this line with 5xFAD mice combined with dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in DAM without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. These models allow either complete cre-loxP targeting of all brain myeloid cells (Cst7Cre), or inducible targeting of DAMs, without leakiness (Cst7DD-Cre).","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481978","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 4

IF 5.4 2区医学

Glia Pub Date : 2025-02-21 DOI: 10.1002/glia.24550

引用次数: 0

Correction to “Early Nuclear Phenotypes and Reactive Transformation in Human iPSC-Derived Astrocytes From ALS Patients With SOD1 Mutations”

IF 5.4 2区医学

Glia Pub Date : 2025-02-17 DOI: 10.1002/glia.70003

引用次数: 0

The Fragile X Messenger Ribonucleoprotein 1 Regulates the Morphology and Maturation of Human and Rat Oligodendrocytes.

IF 5.4 2区医学

Glia Pub Date : 2025-02-10 DOI: 10.1002/glia.24680

Vidya Ramesh, Eleni Tsoukala, Ioanna Kougianou, Zrinko Kozic, Karen Burr, Biju Viswanath, David Hampton, David Story, Bharath Kumar Reddy, Rakhi Pal, Owen Dando, Peter C Kind, Sumantra Chattarji, Bhuvaneish T Selvaraj, Siddharthan Chandran, Lida Zoupi

{"title":"The Fragile X Messenger Ribonucleoprotein 1 Regulates the Morphology and Maturation of Human and Rat Oligodendrocytes.","authors":"Vidya Ramesh, Eleni Tsoukala, Ioanna Kougianou, Zrinko Kozic, Karen Burr, Biju Viswanath, David Hampton, David Story, Bharath Kumar Reddy, Rakhi Pal, Owen Dando, Peter C Kind, Sumantra Chattarji, Bhuvaneish T Selvaraj, Siddharthan Chandran, Lida Zoupi","doi":"10.1002/glia.24680","DOIUrl":"https://doi.org/10.1002/glia.24680","url":null,"abstract":"The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendrocytes, is largely unknown. FXS individuals are characterized by white matter changes, which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell-derived oligodendrocytes and an Fmr1 knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro, which persist in the presence of FMRP-expressing axons in chimeric engraftment models. Our findings point to species-conserved, cell-autonomous defects during oligodendrocyte maturation in FXS.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381349","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

Myelination Trajectory and Microglial Dynamics Following Repeated Sevoflurane Exposure in Developing Brain.

IF 5.4 2区医学

Glia Pub Date : 2025-02-10 DOI: 10.1002/glia.70000

Ji Che, Yuanyuan Wu, Jing Dong, Xuliang Jiang, Li Yang, Yali Chen, Jun Zhang

{"title":"Myelination Trajectory and Microglial Dynamics Following Repeated Sevoflurane Exposure in Developing Brain.","authors":"Ji Che, Yuanyuan Wu, Jing Dong, Xuliang Jiang, Li Yang, Yali Chen, Jun Zhang","doi":"10.1002/glia.70000","DOIUrl":"https://doi.org/10.1002/glia.70000","url":null,"abstract":"The myelination is a critical process during brain development. This study aimed to explore the impact of volatile anesthetic sevoflurane on developing myelination and the role of microglial activation in this process. Neonatal C57BL/6J mice were exposed to sevoflurane at their postnatal 6-8 days. Neurobehavioral tests were used to assess fine motor and cognitive functions. Myelination of hippocampus (HC) and corpus callosum (CC), as well as microglial activation, were determined by western blotting and immunostaining. Lipid droplets were assessed by Oil-Red-O and Bodipy staining. Further, primary microglia were co-cultured with oligodendrocyte precursor cell (OPC) to determine the role of microglia in the proliferation and differentiation of OPC. And microglial inhibitor minocycline and CSF1R inhibitor PLX5622 were administered to assess the effects of microglial activation on developing myelination. The results showed that repeated sevoflurane exposure impaired both fine motor and cognitive functions and induced abnormal expressions of myelin-related proteins myelin basic protein (MBP) and platelet-derived growth factor α receptor (PDGFR-α). And accumulations of lipid droplets were found in the microglia of HC and CC after sevoflurane exposure. Further, the spatiotemporal response to repeated sevoflurane exposure in glial cells exhibited an aberrant myelination process and microglial polarization. The conditioned medium from sevoflurane-treated microglia inhibited the OPC proliferation and differentiation, while minocycline or PLX5622 alleviated sevoflurane-induced neuroinflammation and hypomyelination. Therefore, repeated sevoflurane exposure negatively affected OPC differentiation and myelination trajectory through hyperactivating microglia in developing brain, leading to motor and cognitive impairments, while microglial inhibition/depletion could protect against sevoflurane-induced damage on developing myelination.","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381371","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