NeuroMolecular Medicine最新文献

{"title":"Research Progress on Regulating Neuroinflammation After Spinal Cord Injury by Targeting the cGAS-STING Pathway.","authors":"Nanjian Xu, Weihu Ma, Weixin Dong, Liang Yu","doi":"10.1007/s12017-026-08938-5","DOIUrl":"10.1007/s12017-026-08938-5","url":null,"abstract":"<p><p>Neuroinflammation following secondary injury in spinal cord injury (SCI) constitutes a major obstacle to functional recovery. Endogenous danger signals, particularly mitochondrial DNA (mtDNA) released post-injury, can activate the cGAS-STING pathway, thereby modulating the activation state of microglia and macrophages toward a pro-inflammatory phenotype. This process unfolds within a highly interconnected network involving Toll-like receptor (TLR) signaling, reactive oxygen species (ROS), NLRP3 inflammasome assembly, and cytokine cascades. Through crosstalk with the NLRP3 inflammasome, the cGAS-STING pathway can enhance cellular susceptibility to pyroptosis. The ultimate execution of pyroptotic cell death remains contingent upon additional downstream events, including the activation of Caspase-1 and the cleavage of Gasdermin D. The state of microglia and macrophages is dynamically regulated by a convergence of multiple signaling pathways. Furthermore, the cGAS-STING pathway engages in complex bidirectional interactions with autophagy, underscoring its multifaceted regulatory functions. This review explores emerging intervention strategies targeting this pathway, including small-molecule inhibitors/agonists, genetic interventions, and smart nanomaterials, aimed at achieving precise immunomodulation within the neuroimmune microenvironment. However, the clinical translation of this field still faces significant challenges, primarily concerning issues of spatiotemporal-specific modulation, drug delivery efficiency, and interspecies differences. Future research should focus on elucidating these intricate mechanisms and developing advanced drug delivery systems to facilitate the translation of this therapeutic target from a conceptual framework into clinically effective treatment modalities.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA DLX6-AS1 Regulates the Pathological Process Related to Alzheimer's Disease via miR-204-5p.","authors":"Minggang Jiang, Yang Lin, Liping Wang, Kaiyun Ou","doi":"10.1007/s12017-026-08941-w","DOIUrl":"10.1007/s12017-026-08941-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive neuronal damage. Incidence rises with age, and early diagnosis is difficult. This study examined DLX6-AS1 clinical relevance and regulatory mechanism in AD, and its interaction with miR-204-5p in AD pathology. It offers new insights into early diagnosis and treatment. A total of 133 AD patients and 105 healthy controls were selected. Their serum levels of DLX6-AS1 and miR-204-5p were analyzed using quantitative polymerase chain reaction. β-amyloid (Aβ)_1-42-induced SH-SY5Y neuronal injury and okadaic acid (OA)-induced Neuro-2a tau abnormal phosphorylation models were constructed. The role/function of DLX6-AS1/miR-204-5p axis was then investigated using cell counting kit-8, flow cytometry, western blotting, enzyme-linked immunosorbent assay and a dual-luciferase reporter gene assay. AD patients had higher serum DLX6-AS1 and lower miR-204-5p levels. DLX6-AS1 showed an AUC of 0.838 for AD diagnosis. DLX6-AS1 levels were negatively associated with cognitive function, brain structural integrity, and benign pathology-and positively associated with disease severity, functional impairment, and pathological markers. In AD cell models, DLX6-AS1 was upregulated. Silencing it promoted cell proliferation, reduced apoptosis and oxidative stress, improved mitochondrial and synaptic function, decreased tau phosphorylation, and enhanced microtubule stability and axonal transport. Dual-luciferase assays confirmed direct binding between DLX6-AS1 and miR-204-5p. Co-inhibition reversed the protective effects of DLX6-AS1 silencing. Serum DLX6-AS1 is a potential biomarker for early diagnosis and assessment of AD. It regulates Aβ-induced neuronal damage and tau phosphorylation by targeting miR-204-5p, offering a new mechanism target for AD molecular therapy.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemogenetic Activation of Neurons Promotes Axonal Regeneration and Ameliorates Neurological Deficits in Mice with Intracerebral Hemorrhage by Modulating Mitochondrial Function.","authors":"Jinpeng Wang, Li Zhou, Chunxiao Pang, Hui Liu, Yongli Wang, Zengwu Wang, Wenyuan Ling","doi":"10.1007/s12017-026-08942-9","DOIUrl":"10.1007/s12017-026-08942-9","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a devastating neurological condition characterized by high morbidity and mortality, with limited treatment options for promoting neurological recovery. Enhancing cortical excitability has emerged as a potential strategy for promoting neurological recovery. However, the role of neuronal activation in mitochondrial regulation and axonal regeneration after ICH remains unclear. A chemogenetic approach using adeno-associated virus (AAV)-human M3 muscarinic designer receptor exclusively activated by designer drugs (hM3Dq) was employed to selectively activate cortical excitatory neurons in an ICH mouse model. Behavioral assessments, histological analyses, and molecular evaluations of mitochondrial function and axonal integrity were performed. In vitro, PC12 cells were transfected with hM3Dq and subjected to Hemin-induced injury to assess mitochondrial dynamics and neurite outgrowth. Dynamin-related protein 1 (DRP1) overexpression was used to investigate the role of mitochondrial fission in hM3Dq-mediated effects. hM3Dq activation significantly improved motor and cognitive functions in ICH mice, reduced neuronal apoptosis, and enhanced axonal regeneration. These effects were associated with restored mitochondrial membrane potential, reduced oxidative stress, increased adenosine triphosphate (ATP) production, and partially restored mitochondrial dynamics-related protein expression. In vitro, hM3Dq overexpression mitigated mitochondrial dysfunction and promoted neurite elongation in PC12 cells. Importantly, DRP1 overexpression reversed these beneficial effects, suggesting that inhibition of mitochondrial fission is critical for hM3Dq-mediated neuroprotection. Chemogenetic activation of cortical neurons promotes neurological recovery after ICH and is associated with improved mitochondrial function and enhanced axonal regeneration. Modulation of DRP1-related mitochondrial fission signaling may partially contribute to these effects, suggesting a potential neuron-mitochondria interaction that may serve as a therapeutic target for hemorrhagic stroke.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148592580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep Duration and Epilepsy Risk: Mendelian Randomization and Functional Validation of CACNA1A rs2228130-Related Inhibitory Synaptic Dysfunction.","authors":"Xun Li, Yuying Hou, Yanping Ren, Wei Yue","doi":"10.1007/s12017-026-08943-8","DOIUrl":"10.1007/s12017-026-08943-8","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Objectives To evaluate the causal association between sleep traits and epilepsy risk using Mendelian randomization, and to investigate the mechanism of a prioritized epilepsy-risk variant through gene-level enrichment analysis and functional validation. Methods Large-scale European GWAS datasets were analysed using multiple Mendelian randomization methods, including inverse variance weighted, MR-Egger and weighted median models, with heterogeneity and sensitivity analyses. Epilepsy-associated loci were mapped to protein-coding genes and flanking regions based on GRCh37 annotation, and primary and sensitivity-analysis gene sets were constructed from gene-level summary results for functional enrichment analysis. Guided by locus-level prioritization and the biological plausibility of CACNA1A, rs2228130 was selected for functional validation in CRISPR-ABE-edited human iPSC and knock-in mouse models to assess inhibitory synaptic transmission, sleep-related phenotypes and seizure susceptibility. Results Longer sleep duration was significantly associated with lower epilepsy risk (OR = 0.9937, p &lt; 1 × 10⁻⁵), supporting a protective genetic causal association. The association between insomnia and epilepsy showed substantial heterogeneity (Q = 9352.91) and should be interpreted cautiously. Gene-level enrichment analysis indicated that epilepsy-associated candidate genes converged primarily on broad biological regulation, developmental processes and multicellular organismal processes, without stable dominant enrichment of GABAergic synapse or circadian rhythm pathways. Functional validation showed that rs2228130 did not affect neuronal differentiation but impaired inhibitory synaptic transmission, accompanied by abnormal network activity, altered sleep-related phenotypes and increased seizure susceptibility. Knock-in mice exhibited more frequent epileptiform discharges, reduced non-rapid eye movement sleep, decreased slow-wave activity and altered expression of rhythm-related genes. Pharmacological and sleep-related interventions partially ameliorated these abnormalities. Significance This study supports a protective genetic causal association between longer sleep duration and lower epilepsy risk, and suggests that epilepsy-related genetic risk converges primarily on broad functional networks. Within this framework, functional validation of CACNA1A rs2228130 identifies inhibitory synaptic dysfunction as a key mechanistic node linking genetic risk to sleep- and epilepsy-related phenotypes, providing a rationale for epilepsy prevention and treatment through sleep optimization and targeted modulation of critical downstream pathways. Plain Language Summary We used large-scale genetic data and experimental models to examine how sleep is related to epilepsy. Genetic evidence showed that longer sleep duration was associated with lower epilepsy risk. Although broad gene-level analyses did not identify a stable dominant signal for GABAergic synapse or circadia","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT6 Targets the Autophagy Pathway to Regulate Microglial Senescence in Cognitive Impairment Caused by Cerebral Small-Vessel Disease.","authors":"Xiaolu Liu, Qing Liu, Jingwen Yang, Xia Hu, Xiaoqiu Zhu, Zhan Zhang, You Zuo, Jialin Huang, Lele Wu, Yuhua Fan, Yamei Tang, Zhongshan Shi","doi":"10.1007/s12017-026-08944-7","DOIUrl":"10.1007/s12017-026-08944-7","url":null,"abstract":"<p><p>Cerebral small-vessel disease (CSVD) represents a major etiology of vascular cognitive impairment (VCI), driven by pathological processes such as cellular senescence and neuroinflammation. Among these, microglia-the brain's specialized immune cells-play a key role in driving neuroinflammation through their senescence, thereby exacerbating cognitive dysfunction. Although signal transducer and activator of transcription 6 (STAT6) activation has been implicated in alleviating neuroinflammation and cognitive deficits in CSVD, the underlying mechanisms remain unclear. This study sought to elucidate the roles of STAT6 and autophagy in the process of microglial senescence induced by CSVD. Using stroke-prone renovascular hypertensive rats (RHRSP) and chronic hypoxia-treated BV2 cells to assess cognitive function, microglial senescence, and autophagy, we observed that phosphorylation-mediated STAT6 activation significantly suppressed microglial senescence. Mechanistically, we found that phosphorylated STAT6 (pSTAT6) enhanced autophagy, which reduced the burden of senescent microglia and thereby ameliorated CSVD-induced VCI. These findings provide insights into the potential of targeting the STAT6 pathway in VCI associated with CSVD.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.","authors":"Jiahao Zhang, Quanguang Zhang, J Dedrick Jordan, Xuemei Zong","doi":"10.1007/s12017-026-08924-x","DOIUrl":"10.1007/s12017-026-08924-x","url":null,"abstract":"<p><p>White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13320016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"⁶⁴Cu Hypoxia Imaging Radiotracer Targeting the Human Copper Transporter.","authors":"Shelly Meron, Yulia Shenberger, Ravit Madar, Jana Aupic, Nathalie Abudi, Fabio Lapenta, Melanie Hirsch, Odelia Orbaum Harel, Lukas Hofmann, Alessandra Magistrato, Eitan Okun, Rinat Abramovitch, Sharon Ruthstein","doi":"10.1007/s12017-026-08939-4","DOIUrl":"10.1007/s12017-026-08939-4","url":null,"abstract":"<p><p>The detection and characterization of hypoxia through functional imaging represents a critical frontier in oncology, cardiology, and neurology. Despite extensive efforts, the clinical translation of a robust hypoxia imaging biomarker remains hindered by suboptimal signal limiting diagnostic accuracy. Here, we report the development of a ⁶⁴Cu-based radiotracer (⁶⁴Cu-CysPhe), which exploits the cellular copper uptake pathway involving the human copper transporter 1 (hCtr1). This targeted mechanism facilitates selective tracer accumulation in hypoxic tissues. In-vivo PET-MRI imaging in a murine breast cancer model demonstrated tumor-to-muscle ratios exceeding 3.0 up to 24 h post-injection. Notably, immunohistochemical analyses revealed that ⁶⁴Cu-CysPhe preferentially localizes to hypoxic tumor regions while excluding necrotic cores, thereby providing information about a tumor's immediate microenvironment. Comparative analysis with established radiotracers, including ⁶⁴Cu-ATSM and ¹⁸F-FDG, confirmed the sensitivity of ⁶⁴Cu-CysPhe in detecting hypoxic tumor regions. These findings establish ⁶⁴Cu-CysPhe as a promising candidate for non-invasive imaging of tumors.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curculigoside Alleviates CSDS-induced Depressive-like Behavior by Modulating Pyramidal Neuron Excitability and Synaptic Transmission.","authors":"Yuhong Jing, Tianshu Zhang, Zihao Wei, Huaiyuan Wang, Tianqi Gao, Yanling Liu, Lin Cong, Lianbin Zhao, Shuoxin Xie, Lu Liu, Xinmeng Zhang, Tongrui Wu, Hao Wu, Yuanyuan Li","doi":"10.1007/s12017-026-08926-9","DOIUrl":"10.1007/s12017-026-08926-9","url":null,"abstract":"<p><p>Curculigoside (CUR), a flavonoid derived from traditional Chinese medicine, has shown potential in alleviating depressive symptoms. However, the mechanisms underlying its antidepressant effects remain unclear. The aim of this study was to investigate the effect of CUR on depressive-like behavior in the chronic social defeat stress (CSDS) model and its potential mechanism of action on pyramidal neuronal excitability and synaptic transmission. We injected 20 mg/kg of CUR intraperitoneally for seven days and found that CUR significantly alleviated emotional deficits in mice subjected to CSDS. CUR restored the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) and ventral CA1 (vCA1) regions, which were suppressed by CSDS during depression-like behaviors. Through network pharmacology and molecular docking, we identified CUR's pharmacological targets and found that its antidepressant effects are partly mediated by modulating the cAMP-PKA signaling pathway. CUR treatment ameliorated synaptic transmission dysfunction in both the mPFC and vCA1. CUR regulated the cAMP-PKA signaling pathway and GluA1 subunit trafficking, thereby contributing to the restoration of synaptic function. CUR alleviated depression-like behaviors induced by CSDS by modulating the excitability and synaptic transmission of pyramidal neurons in the mPFC and vCA1 through activation of the cAMP-PKA-GluA1 signaling pathway. These findings provide new insights into CUR's antidepressant mechanisms and highlight its potential as a therapeutic agent for depression.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Cathepsin Proteins with Alzheimer's Disease Risk: An Integrated Observational and Genetic Analysis.","authors":"Qianlong Zhang, Qingyang Li, Zisheng Ai, Fei Li, Yi Wang, Wei Zhou","doi":"10.1007/s12017-026-08933-w","DOIUrl":"10.1007/s12017-026-08933-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) involves complex lysosomal proteolytic dysfunction, but the specific roles of cathepsin family proteins remain unclear. This study aimed to systematically evaluate the association of cathepsins with AD risk and to explore underlying mechanistic pathways integrating neuroimaging, cognitive, and genetic evidence. We analyzed data from 52,988 UK Biobank participants. Plasma levels of 11 cathepsins were measured via Olink proteomics. Associations with AD diagnosis, cognitive performance, and brain structural measures were assessed using multivariable regression. Mediation analysis tested pathways through cognition and brain structure. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential directional associations, and colocalization analysis was performed to identify shared genetic signals. Among the cathepsins analyzed, CTSL was the most coherent signal across observational analyses, showing associations with AD diagnosis, poorer cognitive performance, and reduced volume in AD-vulnerable regions including the hippocampus. Exploratory mediation analyses identified indirect associational patterns involving cognition and brain structure. Bidirectional MR provided genetic evidence for a positive directional association of genetically predicted CTSL with AD diagnosis (β = 1.2666 on the log-odds scale, p < 0.001) and for a reverse association of AD liability with higher CTSL levels (β = 0.5556, p < 0.001). Colocalization initially suggested a shared signal in the APOE/ZNF285 region, but this signal was not independent of APOE after sensitivity analysis. CTSL emerged as a candidate plasma molecule associated with AD across observational and genetic analyses. These findings support further longitudinal and experimental evaluation of CTSL, while the mechanistic interpretation remains preliminary.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell Transcriptomics Reveals that the SORBS1/FBXO22/BAG3 Axis Drives Astrocyte Senescence via Calcium Signaling and Affects Alzheimer's Disease-Related Neuronal Damage.","authors":"Yan Li, Xindong He","doi":"10.1007/s12017-026-08937-6","DOIUrl":"10.1007/s12017-026-08937-6","url":null,"abstract":"<p><p>In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca²⁺ with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}