Neurobiology of Disease最新文献

{"title":"Sex shapes phenotype-linked metabolic signatures of stress exposure in the mouse hypothalamus and pituitary","authors":"Lili Wang ,&nbsp;Bingtao Jiang ,&nbsp;Xunan Ji ,&nbsp;Jiaxin Tu ,&nbsp;Fengmei Lu ,&nbsp;Chen Yang ,&nbsp;Xianhui Zhong ,&nbsp;Lu Wang ,&nbsp;Xiao Cai ,&nbsp;Faping Yi ,&nbsp;Zongling He ,&nbsp;Liang Xie ,&nbsp;Jian Zhou","doi":"10.1016/j.nbd.2025.106898","DOIUrl":"10.1016/j.nbd.2025.106898","url":null,"abstract":"<div><div>In chronic stress-induced anxiodepression, sex differences in the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis are well-documented, yet the underlying molecular mechanisms remain largely unexplored. This study investigated sex-specific metabolic signatures associated with stress exposure in the hypothalamus and pituitary, given the potential significance of brain metabolism in sex-related mechanisms underlying anxiodepression. Utilizing a chronic restraint stress (CRS) model, we conducted a comparative analysis of the metabolic profiles in female and male mice to identify distinct phenotypic expressions related to sex differences. Our findings revealed that metabolite alterations in the pituitary were more pronounced than those in the hypothalamus, indicating significant sex-based variations. These differences facilitated phenotypic differentiation and underscored the relevance of sex-specific metabolic changes and their functional associations to behavioral phenotypes. Moreover, diverging and converging pathways were identified to elucidate the molecular and physiological bases of stress susceptibility in both sexes. Key metabolic and immune-related pathways in the hypothalamus and pituitary, such as histidine, tryptophan, lipid, glycerophospholipid, amino acid, and carbohydrate metabolism, showed specific associations with sex and phenotype. Additionally, correlation analysis uncovered several differential metabolites that were significantly linked to mouse behaviors, with marked sex differences. Collectively, our results demonstrate a pronounced sexual dimorphism at the metabolic level in the hypothalamus and pituitary in response to chronic stress. This study provides a valuable molecular resource for further exploration of the interplay between sex and behavioral phenotypes within the dysregulation of the HPA axis that contributes to stress susceptibility and immune response, emphasizing the critical role of sex-specific metabolic mechanisms in anxiodepressive disorder.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106898"},"PeriodicalIF":5.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788678","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":"Exploring potential key genes and disease mechanisms in Εarly-onset genetic epilepsy via integrated bioinformatics analysis.","authors":"Vasiliki Boulaki, Spiros Efthimiopoulos, Nicholas K Moschonas, George Μ Spyrou","doi":"10.1016/j.nbd.2025.106888","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106888","url":null,"abstract":"<p><p>Epilepsy is a severe common neurological disease affecting all ages. Epilepsy with onset before the age of 5 years, designated early-onset epilepsy (EOE), is of special importance. According to previous studies, genetic factors contribute significantly to the pathogenesis of EOE that remains unclear and must be explored. So, a list of 229 well-selected EOE-associated genes expressed in the brain was created for the investigation of genetic factors and molecular mechanisms involved in its pathogenesis. Enrichment analysis showed that among significant pathways were nicotine addiction, GABAergic synapse, synaptic vesicle cycle, regulation of membrane potential, cholinergic synapse, dopaminergic synapse, and morphine addiction. Performing an integrated analysis as well as protein-protein interaction network-based approaches with the use of GO, KEGG, ClueGO, cytoHubba and 3 network metrics, 12 hub genes were identified, seven of which, CDKL5, GABRA1, KCNQ2, KCNQ3, SCN1A, SCN8A and STXBP1, were identified as key genes (via Venn diagram analysis). These key genes are mostly enriched in SNARE interactions in vesicular transport, regulation of membrane potential and synaptic vesicle exocytosis. Clustering analysis of the PPI network via MCODE showed significant functional modules, indicating also other pathways such as N-Glycan biosynthesis and protein N-linked glycosylation, retrograde endocannabinoid signaling, mTOR signaling and aminoacyl-tRNA biosynthesis. Drug-gene interaction analysis identified a number of drugs as potential medications for EOE, among which the non-FDA approved drugs azetukalner (under clinical development), indiplon and ICA-105665 and the FDA approved drugs retigabine, ganaxolone and methohexital.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106888"},"PeriodicalIF":5.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780618","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":"Excessive expression of progranulin leads to neurotoxicity rather than neuroprotection","authors":"Shinya Kusakari ,&nbsp;Hiroaki Suzuki ,&nbsp;Mikiro Nawa ,&nbsp;Katsuko Sudo ,&nbsp;Rio Yamazaki ,&nbsp;Tamami Miyagi ,&nbsp;Tomoko Ohara ,&nbsp;Masaaki Matsuoka ,&nbsp;Kohsuke Kanekura","doi":"10.1016/j.nbd.2025.106895","DOIUrl":"10.1016/j.nbd.2025.106895","url":null,"abstract":"<div><div>Frontotemporal dementia (FTD) is an early onset form of dementia characterized by frontotemporal lobar atrophy accompanied by behavioral, personality, language, and motor deficits. Heterozygous mutations in <em>GRN</em> gene encoding progranulin (PGRN) are the genetic causes of FTD. Since PGRN is a neurotrophic and anti-inflammatory factor, most FTD-related PGRN mutations are thought to cause FTD due to haploinsufficiency. Therefore, therapies that increase PGRN levels by the administration of recombinant PGRN or viral vectors are attracting attention as an approach to the treatment of FTD. However, the mechanisms underlying the neuroprotective effects of PGRN remain unclear. To investigate the neuroprotective mechanisms of PGRN <em>in vivo</em>, we generated human PGRN transgenic (Tg) mice using the CAG promoter. Unexpectedly, mice overexpressing wild-type human PGRN showed a shortened lifespan and cerebellar dysfunction, including the loss of Purkinje cells. Furthermore, PGRN Tg mice developed cognitive impairment, gliosis, and lysosomal abnormalities. FTD-causative R432C-PGRN mutant Tg mice also showed FTD-like phenotypes, such as neuronal loss, gliosis, and behavioral deficits. In cultured cells, overexpression of PGRN induced endoplasmic reticulum (ER) stress and apoptotic cell death, suggesting that continuous increases in PGRN expression through viral vectors or genetic manipulation are neurotoxic and that PGRN-replacement therapy may be required to maintain optimal PGRN levels for each neuron type and brain region.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106895"},"PeriodicalIF":5.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780617","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":"Apolipoproteins in ischemic stroke progression and recovery: Key molecular mechanisms and therapeutic potential","authors":"Tamara Etuze ,&nbsp;Hortense Triniac ,&nbsp;Ze Zheng ,&nbsp;Denis Vivien ,&nbsp;Fatemeh Dubois","doi":"10.1016/j.nbd.2025.106896","DOIUrl":"10.1016/j.nbd.2025.106896","url":null,"abstract":"<div><div>Ischemic stroke, responsible for 80 % of all strokes, is a leading cause of mortality globally. While altered lipids profiles are recognized as modifiable risk factors, their direct impact on stroke outcomes is less understood due to the brain's distinct lipid metabolism and the selective permeability of the blood-brain barrier for lipoproteins. As key components of lipoproteins, apolipoproteins are essential for lipid transport, redistribution and metabolism in both the central nervous system and peripheral blood circulation. This review provides an updated perspective on the influence of brain-expressed apolipoproteins (such as ApoE, ApoA-I, ApoJ, ApoD, and others) and those that cross the damaged blood-brain barrier following ischemic stroke. We explore hypotheses regarding their involvement in molecular pathways related to lipid metabolism, inflammation, oxidative stress, mitochondrial function and blood-brain barrier integrity. Through this synthesis, we aim to identify potential biomarkers and therapeutic targets, thereby enhancing our understanding of apolipoproteins in ischemic stroke progression and contributing to improved clinical outcomes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106896"},"PeriodicalIF":5.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769167","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":"Regenerative failure of sympathetic axons contributes to deficits in functional recovery after nerve injury","authors":"Tina Tian ,&nbsp;David Kim ,&nbsp;Kuai Yu ,&nbsp;H. Criss Hartzell ,&nbsp;Patricia J. Ward","doi":"10.1016/j.nbd.2025.106893","DOIUrl":"10.1016/j.nbd.2025.106893","url":null,"abstract":"<div><div>Renewed scientific interest in sympathetic modulation of muscle and neuromuscular junctions has spurred a flurry of new discoveries with major implications for motor diseases. However, the role sympathetic axons play in the persistent dysfunction that occurs after nerve injuries remains to be explored. Peripheral nerve injuries are common and lead to motor, sensory, and autonomic deficits that result in lifelong disabilities. Given the importance of sympathetic signaling in muscle metabolic health and maintaining bodily homeostasis, it is imperative to understand the regenerative capacity of sympathetic axons after injury. Therefore, we tested sympathetic axon regeneration and functional reinnervation of skin and muscle, both acute and long-term, using a battery of anatomical, pharmacological, chemogenetic, cell culture, analytical chemistry, and electrophysiological techniques. We employed several established growth-enhancing interventions, including electrical stimulation and conditioning lesion, as well as an innovative tool called bioluminescent optogenetics. Our results indicate that sympathetic regeneration is not enhanced by any of these treatments and may even be detrimental to sympathetic regeneration. Despite the complete return of motor reinnervation after sciatic nerve injury, gastrocnemius muscle atrophy and deficits in muscle cellular energy charge, as measured by relative ATP, ADP, and AMP concentrations, persisted long after injury, even with electrical stimulation. We suggest that these long-term deficits in muscle energy charge and atrophy are related to the deficiency in sympathetic axon regeneration. New studies are needed to better understand the mechanisms underlying sympathetic regeneration to develop therapeutics that can enhance the regeneration of all axon types.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106893"},"PeriodicalIF":5.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753694","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":"Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model","authors":"Nisha Plavelil ,&nbsp;Abhilash P. Appu ,&nbsp;K.C. Gopal ,&nbsp;Avisek Mondal ,&nbsp;Neil Perkins ,&nbsp;Anil B. Mukherjee","doi":"10.1016/j.nbd.2025.106890","DOIUrl":"10.1016/j.nbd.2025.106890","url":null,"abstract":"<div><div>Lysosomal storage disorders (LSDs) represent 70 inherited metabolic diseases, in most of which neurodegeneration is a devastating manifestation. The CLN1 disease is a fatal neurodegenerative LSD, caused by inactivating mutations in the <em>CLN1</em> gene encoding palmitoyl-protein thioesterase-1 (PPT1). S-palmitoylation, a reversable posttranslational modification by saturated fatty acids (generally palmitate) facilitates endosomal trafficking of many proteins, especially in the brain. While palmitoyl-acyltransferases (called ZDHHCs) catalyze S-palmitoylation, depalmitoylation is mediated by palmitoyl-protein thioesterases (PPTs). We previously reported that in <em>Cln1</em>^{<em>−/−</em>} mice, which mimic human CLN1-disease, endoplasmic reticulum (ER)-stress leads to unfolded protein response (UPR) contributing to neurodegeneration. However, the mechanism underlying ER-stress has remained elusive. The anterograde (ER to Golgi) protein-trafficking is mediated via COPII (coat protein complex II) vesicles, whereas the retrograde transport (Golgi to ER) is mediated by COPI vesicles. We hypothesized that dysregulated anterograde protein-trafficking causing stagnation of proteins in the ER leads to ER-stress in <em>Cln1</em>^{<em>−/−</em>} mice. We found that the levels of five COPII vesicle-associated proteins (i.e. Sar1, Sec23, Sec24, Sec13 and Sec31) are significantly higher in the ER-fractions of cortical tissues from <em>Cln1</em>^{<em>−/−</em>} mice compared with those from their WT littermates. Remarkably, all COPII proteins, except Sec13, undergo S-palmitoylation. Moreover, CLN8, a Batten disease-protein, requires dynamic S-palmitoylation (palmitoylation-depalmitoylation) for ER-Golgi trafficking. Intriguingly, Ppt1-deficiency in <em>Cln1</em>^{<em>−/−</em>} mice impairs ER-Golgi trafficking of Cln8-protein along with several other COPII-associated proteins. We propose that impaired anterograde trafficking causes excessive accumulation of proteins in the ER causing ER-stress and UPR contributing to neurodegeneration in CLN1 disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106890"},"PeriodicalIF":5.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753693","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":"TIMP-1 associates with myelin membrane and preserves myelin in injured peripheral nerve","authors":"Hanbum Joe ,&nbsp;Hyungseok Seo ,&nbsp;Jennifer Dolkas ,&nbsp;Megh Jawala ,&nbsp;Swathi K. Hullugundi ,&nbsp;Yang Hoon Chung ,&nbsp;Hemal H. Patel ,&nbsp;Andrei V. Chernov ,&nbsp;Veronica I. Shubayev","doi":"10.1016/j.nbd.2025.106892","DOIUrl":"10.1016/j.nbd.2025.106892","url":null,"abstract":"<div><div>Myelin enables rapid impulse propagation in axons across long distances. Following peripheral nerve injury, Schwann cells provide trophic, metabolic, and immune support to damaged neurons. To facilitate myelin repair, Schwann cells activate a robust transcriptional program, including the tissue inhibitor of metalloproteinase (TIMP)-1 gene. TIMP-1 is a potent protease inhibitor and neurotrophic factor, traditionally known as a secreted protein. This study presents the first evidence of a myelin/membrane-associated (mm)TIMP-1 protein fraction in the nervous system. Specifically, we identified mmTIMP-1 in the rat sciatic nerve after chronic constriction injury (CCI) using multiple complementary approaches. Dual-immunofluorescence revealed TIMP-1 co-localization with myelin protein in the myelin sheath of CCI nerve. Immunoblotting and mass-spectrometry of sucrose gradient-fractionated nerves further confirmed presence of TIMP-1 in myelin/membrane lipid rafts. Both TIMP-1 and (mm)TIMP-1 levels increased in the nerves during the early phase (day 1) and declined in the late phase (day 28) of CCI. Recombinant (r)TIMP-1 replacement therapy during the late phase CCI, administered by intraneural injection, led to improved myelin neuropathology and accumulation of myelin protein. This study identifies a novel subcellular TIMP-1 fraction associated with the myelin sheath and highlights TIMP-1's reparative activity in peripheral nerve myelin in vivo, opening new avenues for exploring functional activities of TIMP-1 isoforms in the nervous system.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106892"},"PeriodicalIF":5.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753695","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":"α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease","authors":"Yakum B. Mingo ,&nbsp;Martha L. Escobar Galvis ,&nbsp;Michael X. Henderson","doi":"10.1016/j.nbd.2025.106889","DOIUrl":"10.1016/j.nbd.2025.106889","url":null,"abstract":"<div><div>Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106889"},"PeriodicalIF":5.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743294","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":"Early life seizures chronically disrupt L-type voltage gated calcium channel regulation of mGluR mediated long term depression via interactions with protein phosphatase 2A","authors":"Paul B. Bernard ,&nbsp;Anna M. Castano ,&nbsp;Olivia R. Buonarati ,&nbsp;Chad R. Camp ,&nbsp;Johannes W. Hell ,&nbsp;Tim A. Benke","doi":"10.1016/j.nbd.2025.106884","DOIUrl":"10.1016/j.nbd.2025.106884","url":null,"abstract":"<div><div>We probed the dependence of metabotropic glutamate receptor dependent long-term depression (mGluR-LTD) on L-type voltage gated calcium channels (LTCCs). In prior work, we found that in a rat model of early life seizures (ELS), exaggerated mGluR-LTD was partly mediated by LTCCs and protein phosphatase 2A (PP2A). Here, we further investigated the interactive role of LTCCs, PP2A, and protein kinase A (PKA) in this same model. PP2Ac is known to bind Ca_V1.2 and modulate its function; displacement of PP2A (C subunit, or PP2Ac) as well as PKA phosphorylation of Ca_V1.2 at serine 1928, result in enhanced Ca_V1.2 function. We found that ELS enhanced LTCC activity. We further found that pharmacological displacement of PP2Ac (but not PP2B/calcineurin) from Ca_V1.2 enhanced mGluR-LTD in controls. This was occluded by blockade of PP2A or ELS. The LTCC-dihydropyridine agonist BayK 8644 enhanced mGluR-LTD in controls, which was also occluded by ELS. Up-regulation of both intracellular Ca²⁺ and PKA activity were implicated in ELS enhancement of mGluR-LTD, as LTD was normalized in ELS by depletion of internal calcium stores or blockade of PKA. These results support a dynamic model of mGluR-LTD regulation by LTCCs through PP2Ac binding and phosphorylation by PKA. This regulation is chronically lost after ELS. Together with our prior work, these studies tie hyperactive LTCCs to the chronic ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106884"},"PeriodicalIF":5.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143716082","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":"Astrocyte heterogeneity in ischemic stroke: Molecular mechanisms and therapeutic targets","authors":"Daxing Li ,&nbsp;Xinchen Huo ,&nbsp;Ling Shen ,&nbsp;Minjie Qian ,&nbsp;Jindou Wang ,&nbsp;Shijie Mao ,&nbsp;Wenjing Chen ,&nbsp;Runheng Li ,&nbsp;Tianhao Zhu ,&nbsp;Beicheng Zhang ,&nbsp;Kunxuan Liu ,&nbsp;Feifei Wu ,&nbsp;Ying Bai","doi":"10.1016/j.nbd.2025.106885","DOIUrl":"10.1016/j.nbd.2025.106885","url":null,"abstract":"<div><div>Ischemic stroke is one of the major causes of death and disability in adults, bringing a significant economic burden to the society and families. Despite significant advancements in stroke treatment, focusing solely on neurons is insufficient for improving disease progression and prognosis. Astrocytes are the most ubiquitous cells in the brain, and they undergo morphological and functional changes after brain insults, which has been known as astrocyte reactivity. Transcriptomics have shown that reactive astrocytes (RA) are heterogeneous, and they can be roughly classified into neurotoxic and neuroprotective types, thereby affecting the development of central nervous system (CNS) diseases. However, the relationship between stroke and reactive astrocyte heterogeneity has not been fully elucidated, and regulating the heterogeneity of astrocytes to play a neuroprotective role may provide a new perspective for the treatment of stroke. Here we systematically review current advancements in astrocyte heterogeneity following ischemic stroke, elucidate the molecular mechanisms underlying their activation, and further summarize promising therapeutic agents and molecular targets capable of modulating astrocyte heterogeneity.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106885"},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730548","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}