Neutrophils are increasingly recognized as pivotal contributors to the ischemic stroke cascade, influencing disease progression, thrombolysis outcomes, and patient prognosis. Epidemiological evidence consistently links neutrophil counts with the incidence of ischemic stroke. Pathophysiologically, neutrophils play critical roles in disrupting blood-brain barrier, amplifying inflammatory responses, and promoting thrombotic processes. Understanding their role is crucial for developing targeted therapies to improve stroke outcomes. This review focuses on the role of neutrophils in ischemic stroke, covering epidemiology, pathophysiological mechanisms, historical perspectives, interactions with rt-PA thrombolysis, clinical implications, controversies, challenges, and future directions.
{"title":"From first responders to outcome modulators: The evolving paradigm of neutrophils in ischemic stroke and thrombolysis","authors":"Jiawei Wu , Zheng Huang , Siqi Chang , Zihao Peng , Zixuan Fang , Guangxia Ni , Yawen Xia","doi":"10.1016/j.expneurol.2025.115611","DOIUrl":"10.1016/j.expneurol.2025.115611","url":null,"abstract":"<div><div>Neutrophils are increasingly recognized as pivotal contributors to the ischemic stroke cascade, influencing disease progression, thrombolysis outcomes, and patient prognosis. Epidemiological evidence consistently links neutrophil counts with the incidence of ischemic stroke. Pathophysiologically, neutrophils play critical roles in disrupting blood-brain barrier, amplifying inflammatory responses, and promoting thrombotic processes. Understanding their role is crucial for developing targeted therapies to improve stroke outcomes. This review focuses on the role of neutrophils in ischemic stroke, covering epidemiology, pathophysiological mechanisms, historical perspectives, interactions with rt-PA thrombolysis, clinical implications, controversies, challenges, and future directions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115611"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833500","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}
Pub Date : 2025-12-23DOI: 10.1016/j.expneurol.2025.115613
Jun Fu , Chengjie Ding , Wenqing Li , Jiali Lei , He Wang , Lingfei Meng , Xiaoya Lin , Weiyuan Chen , Hongchang Gao
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including Aβ deposition and tau protein hyperphosphorylation. These pathological alterations are particularly prominent in the Prefrontal Cortex (PFC) and exert profound effects on cognitive function. The present study aimed to reveal key proteins in the PFC and provide insight into their potential mechanisms of action in AD. Accordingly, proteomic analysis was conducted to profile differential proteins in 5 × FAD mice, followed by in vivo and in vitro validation of core proteins through AAV-mediated interference of target gene expression. Furthermore, transcriptomics and molecular biology techniques were employed to confirm the underlying mechanisms of action of core proteins in AD. The results demonstrated that ELAVL1 was significantly upregulated in the PFC of AD mice. Behavioral experiments revealed that inhibition of ELAVL1 expression markedly improved long-term memory in AD mice. Immunostaining and Western blot analyses confirmed that suppressing ELAVL1 expression alleviated Aβ1–42 deposition and apoptosis. In vitro experiments indicated that knocking down ELAVL1 significantly reduced the apoptotic response of SH-SY5Y cells induced by Aβ1–42 and APP/Swe cells. Transcriptomic analysis further revealed that ELAVL1 regulates Aβ1–42-induced apoptosis via activation of the Bcl-2/Bax pathway. Notably, immunofluorescence co-localization staining and pull-down assays confirmed that ELAVL1 directly interacts with APP. Collectively, these findings provide valuable insights into the molecular mechanisms underlying AD and suggest ELAVL1 as a promising therapeutic target for AD.
{"title":"ELAVL1 interacts with APP and promotes Aβ-induced apoptosis in Alzheimer's disease by activating Bcl-2/Bax signaling","authors":"Jun Fu , Chengjie Ding , Wenqing Li , Jiali Lei , He Wang , Lingfei Meng , Xiaoya Lin , Weiyuan Chen , Hongchang Gao","doi":"10.1016/j.expneurol.2025.115613","DOIUrl":"10.1016/j.expneurol.2025.115613","url":null,"abstract":"<div><div>Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including Aβ deposition and tau protein hyperphosphorylation. These pathological alterations are particularly prominent in the Prefrontal Cortex (PFC) and exert profound effects on cognitive function. The present study aimed to reveal key proteins in the PFC and provide insight into their potential mechanisms of action in AD. Accordingly, proteomic analysis was conducted to profile differential proteins in 5 × FAD mice, followed by <em>in vivo</em> and <em>in vitro</em> validation of core proteins through AAV-mediated interference of target gene expression. Furthermore, transcriptomics and molecular biology techniques were employed to confirm the underlying mechanisms of action of core proteins in AD. The results demonstrated that ELAVL1 was significantly upregulated in the PFC of AD mice. Behavioral experiments revealed that inhibition of ELAVL1 expression markedly improved long-term memory in AD mice. Immunostaining and Western blot analyses confirmed that suppressing ELAVL1 expression alleviated Aβ1–42 deposition and apoptosis. <em>In vitro</em> experiments indicated that knocking down ELAVL1 significantly reduced the apoptotic response of SH-SY5Y cells induced by Aβ1–42 and APP/Swe cells. Transcriptomic analysis further revealed that ELAVL1 regulates Aβ1–42-induced apoptosis <em>via</em> activation of the Bcl-2/Bax pathway. Notably, immunofluorescence co-localization staining and pull-down assays confirmed that ELAVL1 directly interacts with APP. Collectively, these findings provide valuable insights into the molecular mechanisms underlying AD and suggest ELAVL1 as a promising therapeutic target for AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115613"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833495","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}
Pub Date : 2025-12-23DOI: 10.1016/j.expneurol.2025.115604
Stefan J. Blaschke , Heiko Backes , Susan Vlachakis , Nora Rautenberg , Seda Demir , Dirk Wiedermann , Markus Aswendt , Gereon R. Fink , Michael Schroeter , Maria A. Rueger
Transcranial direct current stimulation (tDCS) is a clinically promising neuromodulatory therapy, capable of promoting function and motor recovery after stroke. Beyond the primary stroke lesion, remote networks disturbances, e.g., stroke-induced secondary neurodegeneration (SND), are related to long-term disabilities. Under the hypothesis that tDCS promotes recovery by supporting neuroprotection, we investigated the effects of tDCS on thalamic SND after stroke.
Three days after cortical stroke, induced by photothrombosis, cathodal tDCS over the lesioned cortex was performed daily for ten days (39.6 kC/m2). SND, i.e., neuronal loss, and inflammation in the ipsilesional thalamus were evaluated ex vivo 28 days after stroke. Parameters of functional thalamic network integration measured by resting-state functional magnetic resonance imaging (rs-fMRI) were conducted longitudinally. To assess the effects of tDCS on glucose metabolism, positron emission tomography (PET) was performed after a similar tDCS regimen in healthy mice.
Repetitive tDCS decreased the ipsilateral thalamic glucose metabolism in unlesioned animals. Four weeks after cortical stroke, secondary glial scaring was found in the ipsilesional thalamus, its extent correlating to the cortical lesion size (R2 = 0.54, p < 0.001). Notably, while it did not affect glial scaring, tDCS reduced thalamic neurodegeneration by over 60 % (p < 0.05), being reflected by parameters of functional thalamic integration as assessed by rs-fMRI. Additionally, tDCS downregulated the pro-inflammatory polarization of microglia.
Overall, tDCS ameliorated the stroke-induced remote SND, in parallel to mitigating sustained neuroinflammation. Thus, the data show that tDCS exerts previously unknown effects on remote brain regions after stroke.
{"title":"Subacute cathodal transcranial direct current stimulation rescues secondary thalamic neurodegeneration after cortical stroke in mice","authors":"Stefan J. Blaschke , Heiko Backes , Susan Vlachakis , Nora Rautenberg , Seda Demir , Dirk Wiedermann , Markus Aswendt , Gereon R. Fink , Michael Schroeter , Maria A. Rueger","doi":"10.1016/j.expneurol.2025.115604","DOIUrl":"10.1016/j.expneurol.2025.115604","url":null,"abstract":"<div><div>Transcranial direct current stimulation (tDCS) is a clinically promising neuromodulatory therapy, capable of promoting function and motor recovery after stroke. Beyond the primary stroke lesion, remote networks disturbances, e.g., stroke-induced secondary neurodegeneration (SND), are related to long-term disabilities. Under the hypothesis that tDCS promotes recovery by supporting neuroprotection, we investigated the effects of tDCS on thalamic SND after stroke.</div><div>Three days after cortical stroke, induced by photothrombosis, cathodal tDCS over the lesioned cortex was performed daily for ten days (39.6 kC/m<sup>2</sup>). SND, i.e., neuronal loss, and inflammation in the ipsilesional thalamus were evaluated ex vivo 28 days after stroke. Parameters of functional thalamic network integration measured by resting-state functional magnetic resonance imaging (rs-fMRI) were conducted longitudinally. To assess the effects of tDCS on glucose metabolism, positron emission tomography (PET) was performed after a similar tDCS regimen in healthy mice.</div><div>Repetitive tDCS decreased the ipsilateral thalamic glucose metabolism in unlesioned animals. Four weeks after cortical stroke, secondary glial scaring was found in the ipsilesional thalamus, its extent correlating to the cortical lesion size (R<sup>2</sup> = 0.54, <em>p</em> < 0.001). Notably, while it did not affect glial scaring, tDCS reduced thalamic neurodegeneration by over 60 % (<em>p</em> < 0.05), being reflected by parameters of functional thalamic integration as assessed by rs-fMRI. Additionally, tDCS downregulated the pro-inflammatory polarization of microglia.</div><div>Overall, tDCS ameliorated the stroke-induced remote SND, in parallel to mitigating sustained neuroinflammation. Thus, the data show that tDCS exerts previously unknown effects on remote brain regions after stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115604"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833450","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}
Pub Date : 2025-12-19DOI: 10.1016/j.expneurol.2025.115600
Maximilian Keller , Celine Gallagher , Liana Marengo , Kira Bickenbach , Ulrich Schmitt , Mohammad Abukhalaf , Andreas Tholey , Simon Kreiselmaier , Christoph Becker-Pauly , Thomas Mittmann , Claus U. Pietrzik
The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.
{"title":"Meprin β elevates hippocampal soluble Aβ in the APP/V717I mouse model","authors":"Maximilian Keller , Celine Gallagher , Liana Marengo , Kira Bickenbach , Ulrich Schmitt , Mohammad Abukhalaf , Andreas Tholey , Simon Kreiselmaier , Christoph Becker-Pauly , Thomas Mittmann , Claus U. Pietrzik","doi":"10.1016/j.expneurol.2025.115600","DOIUrl":"10.1016/j.expneurol.2025.115600","url":null,"abstract":"<div><div>The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115600"},"PeriodicalIF":4.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803435","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}
Pub Date : 2025-12-17DOI: 10.1016/j.expneurol.2025.115599
Shaoting Jia , Mo Liu , Ding Nan, Lu Yang, Jing Zhang, Jing Yang, Xuehua Liu
Hyperbaric oxygen (HBO) suppresses the inflammatory response following spinal cord injury (SCI). However, the underlying detailed mechanisms are still to be clarified. Here we explored the mechanism of long non-coding RNA (lncRNA) glutathione s-transferase mu 5 (Gstm5) regulating NF-κB signaling pathway in HBO-mediated suppression of inflammatory response following SCI. In the current study, SCI cell model was developed with lipopolysaccharides (LPS)-induced BV2 cells and processed with HBO treatment, si-NC, and si-Lnc-Gstm5. Lnc-Gstm5, NF-κB p65, IL-1β，IL-6, TNF-a, suppressor of variegation 3–9 homolog 1 (SUV39H1), histone 3 lysine 9 trimethylation (H3K9me3), YTH domain containing 2 (YTHDC2) expression level were measured. The mice SCI model was generated and treated with HBO treatment, shRNA-Lnc-Gstm5. Lnc-Gstm5 was identified and BMS score, histopathological injury score, and inflammatory factors were evaluated. We found that HBO suppresses inflammatory response through up-regulating Lnc-Gstm5 level in a manner of YTHDC2-dependent m6A modification. Lnc-Gstm5 recruits SUV39H1 to up-regulate H3K9me3 expression level and suppresses NF-κB signaling pathway by reducing p65 phosphorylation. HBO suppresses the inflammatory response via YTHDC2/Lnc-Gstm5/SUV39H1/H3K9me3/NF-κB axis following SCI in mice. These results reveal a Lnc-Gstm5-driven epigenetic regulation mechanism, and targeting Lnc-Gstm5 represents a promising therapeutic strategy for SCI patients.
{"title":"Mechanistic study on Lnc-Gstm5 regulation of the SUV39H1/H3K9me3 axis in hyperbaric oxygen-mediated suppression of inflammatory response following spinal cord injury","authors":"Shaoting Jia , Mo Liu , Ding Nan, Lu Yang, Jing Zhang, Jing Yang, Xuehua Liu","doi":"10.1016/j.expneurol.2025.115599","DOIUrl":"10.1016/j.expneurol.2025.115599","url":null,"abstract":"<div><div>Hyperbaric oxygen (HBO) suppresses the inflammatory response following spinal cord injury (SCI). However, the underlying detailed mechanisms are still to be clarified. Here we explored the mechanism of long non-coding RNA (lncRNA) glutathione s-transferase mu 5 (Gstm5) regulating NF-κB signaling pathway in HBO-mediated suppression of inflammatory response following SCI. In the current study, SCI cell model was developed with lipopolysaccharides (LPS)-induced BV2 cells and processed with HBO treatment, si-NC, and si-Lnc-Gstm5. Lnc-Gstm5, NF-κB p65, IL-1β，IL-6, TNF-a, suppressor of variegation 3–9 homolog 1 (SUV39H1), histone 3 lysine 9 trimethylation (H3K9me3), YTH domain containing 2 (YTHDC2) expression level were measured. The mice SCI model was generated and treated with HBO treatment, shRNA-Lnc-Gstm5. Lnc-Gstm5 was identified and BMS score, histopathological injury score, and inflammatory factors were evaluated. We found that HBO suppresses inflammatory response through up-regulating Lnc-Gstm5 level in a manner of YTHDC2-dependent m6A modification. Lnc-Gstm5 recruits SUV39H1 to up-regulate H3K9me3 expression level and suppresses NF-κB signaling pathway by reducing p65 phosphorylation. HBO suppresses the inflammatory response via YTHDC2/Lnc-Gstm5/SUV39H1/H3K9me3/NF-κB axis following SCI in mice. These results reveal a Lnc-Gstm5-driven epigenetic regulation mechanism, and targeting Lnc-Gstm5 represents a promising therapeutic strategy for SCI patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115599"},"PeriodicalIF":4.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793704","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}
Pub Date : 2025-12-17DOI: 10.1016/j.expneurol.2025.115601
Meixiang Zhou , Yuechun Yang , Shiyong Wang, Jing Zhang
Background: Sleep deprivation (SD) is highly prevalent among the elderly population and accelerates cognitive decline through mechanisms such as neuroinflammation and disruption of the gut-brain axis. This study aims to investigate whether Ophiopogon polysaccharides (OPS) can improve memory impairment induced by SD in aged rats by modulating the gut microbiota and inhibiting the TLR4/NF-κB pathway in the hippocampus. A modified multi-platform method was employed to administer treatment to 20-month-old male Sprague-Dawley rats following seven days of sleep deprivation. The Morris water maze test, HE staining, ELISA, 16S rRNA sequencing, and Western blotting were conducted for histological and molecular biological analyses.The anti-inflammatory and neuroprotective effects of OPS were further validated in LPS-stimulated BV2 microglial cells and a BV2-HT22 co-culture system. The results demonstrated that OPS significantly ameliorated spatial memory deficits in sleep-deprived rats, alleviated hippocampal neuronal damage, reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and restored the balance of neurotransmitters (DA, 5-HT). 16S rRNA sequencing revealed that OPS modulated the gut microbiota structure, increased the abundance of potential probiotic taxa such as norank_f__Muribaculaceae and Faecalibacterium, and decreased the abundance of potential pro-inflammatory genera such as Oscillibacter and Romboutsia. Western blot analysis indicated that OPS inhibited the activation of the TLR4/NF-κB signaling pathway in the hippocampus. In vitro experiments confirmed that OPS could inhibit the LPS-induced inflammatory response in BV2 microglial cells and reduce microglia-mediated neuronal apoptosis in HT22 cells. These findings suggest that OPS may serve as a promising therapeutic agent for mitigating cognitive impairment caused by sleep deprivation, exerting its effects through multi-target mechanisms, including modulation of gut microbiota and suppression of hippocampal TLR4/NF-κB-mediated neuroinflammatory pathways.
{"title":"Ophiopogon polysaccharide can improve memory impairment induced by sleep deprivation in aged rats by regulating gut microbiota and inhibiting TLR4/NF-κB pathway in hippocampus","authors":"Meixiang Zhou , Yuechun Yang , Shiyong Wang, Jing Zhang","doi":"10.1016/j.expneurol.2025.115601","DOIUrl":"10.1016/j.expneurol.2025.115601","url":null,"abstract":"<div><div>Background: Sleep deprivation (SD) is highly prevalent among the elderly population and accelerates cognitive decline through mechanisms such as neuroinflammation and disruption of the gut-brain axis. This study aims to investigate whether Ophiopogon polysaccharides (OPS) can improve memory impairment induced by SD in aged rats by modulating the gut microbiota and inhibiting the TLR4/NF-κB pathway in the hippocampus. A modified multi-platform method was employed to administer treatment to 20-month-old male Sprague-Dawley rats following seven days of sleep deprivation. The Morris water maze test, HE staining, ELISA, 16S rRNA sequencing, and Western blotting were conducted for histological and molecular biological analyses.The anti-inflammatory and neuroprotective effects of OPS were further validated in LPS-stimulated BV2 microglial cells and a BV2-HT22 co-culture system. The results demonstrated that OPS significantly ameliorated spatial memory deficits in sleep-deprived rats, alleviated hippocampal neuronal damage, reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and restored the balance of neurotransmitters (DA, 5-HT). 16S rRNA sequencing revealed that OPS modulated the gut microbiota structure, increased the abundance of potential probiotic taxa such as norank_f__Muribaculaceae and Faecalibacterium, and decreased the abundance of potential pro-inflammatory genera such as Oscillibacter and Romboutsia. Western blot analysis indicated that OPS inhibited the activation of the TLR4/NF-κB signaling pathway in the hippocampus. In vitro experiments confirmed that OPS could inhibit the LPS-induced inflammatory response in BV2 microglial cells and reduce microglia-mediated neuronal apoptosis in HT22 cells. These findings suggest that OPS may serve as a promising therapeutic agent for mitigating cognitive impairment caused by sleep deprivation, exerting its effects through multi-target mechanisms, including modulation of gut microbiota and suppression of hippocampal TLR4/NF-κB-mediated neuroinflammatory pathways.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115601"},"PeriodicalIF":4.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793077","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}
Pub Date : 2025-12-16DOI: 10.1016/j.expneurol.2025.115598
Zhongwu Liu , Mikkala Mccann , Brianna Powell , Julie Landschoot-Ward , Zheng Gang Zhang , Michael Chopp
Background
Multi-infarct dementia (MID), a severe form of vascular cognitive impairment, results from cumulative impact of multiple cerebral microinfarcts (MMIs). Current preclinical models primarily rely on unilateral induction of MMIs, which fails to reproduce bilateral lesion distribution and persistent cognitive decline characteristic of human disease.
Objective
To develop and characterize a modified bilateral MMI model that more accurately reflects the clinical and pathological features of MID.
Methods
Twelve-month-old male C57BL/6J mice underwent either unilateral or bilateral MMI induction by microsphere embolization via the internal carotid artery. Bilateral induction was achieved by transiently occluding the contralateral common carotid artery during microsphere infusion. Behavioral assessments using novel object recognition (NOR) and elevated plus maze (EPM) were conducted on days 7, 14, and 28 post-surgery. Histological Hematoxylin and Eosin staining and immunohistochemical analyses using antibodies against Iba1 and GFAP were performed to evaluate lesion distribution and neuroinflammation.
Results
The modified bilateral procedure successfully induced widespread infarcts across both hemispheres. Bilateral MMI mice exhibited significantly greater and persistent cognitive impairment, demonstrated by a reduced NOR discrimination index and decreased open-arm exploration in the EPM persisting through day 28, than did unilateral MMI mice. Histological analysis confirmed bilateral microinfarcts and significant increase in Iba1- and GFAP-positive staining, indicating robust and sustained bilateral neuroinflammation.
Conclusion
This modified bilateral MMI procedure reproduces key pathological and functional features of human MID, overcoming the limitations of traditional unilateral models. The new model provides a clinically relevant platform for investigating mechanisms underlying vascular cognitive impairment and evaluating potential disease-modifying therapies.
{"title":"A new microinfarcts model produces widespread bilateral infarcts and persistent cognitive deficits in middle-aged mice","authors":"Zhongwu Liu , Mikkala Mccann , Brianna Powell , Julie Landschoot-Ward , Zheng Gang Zhang , Michael Chopp","doi":"10.1016/j.expneurol.2025.115598","DOIUrl":"10.1016/j.expneurol.2025.115598","url":null,"abstract":"<div><h3>Background</h3><div>Multi-infarct dementia (MID), a severe form of vascular cognitive impairment, results from cumulative impact of multiple cerebral microinfarcts (MMIs). Current preclinical models primarily rely on unilateral induction of MMIs, which fails to reproduce bilateral lesion distribution and persistent cognitive decline characteristic of human disease.</div></div><div><h3>Objective</h3><div>To develop and characterize a modified bilateral MMI model that more accurately reflects the clinical and pathological features of MID.</div></div><div><h3>Methods</h3><div>Twelve-month-old male C57BL/6J mice underwent either unilateral or bilateral MMI induction by microsphere embolization via the internal carotid artery. Bilateral induction was achieved by transiently occluding the contralateral common carotid artery during microsphere infusion. Behavioral assessments using novel object recognition (NOR) and elevated plus maze (EPM) were conducted on days 7, 14, and 28 post-surgery. Histological Hematoxylin and Eosin staining and immunohistochemical analyses using antibodies against Iba1 and GFAP were performed to evaluate lesion distribution and neuroinflammation.</div></div><div><h3>Results</h3><div>The modified bilateral procedure successfully induced widespread infarcts across both hemispheres. Bilateral MMI mice exhibited significantly greater and persistent cognitive impairment, demonstrated by a reduced NOR discrimination index and decreased open-arm exploration in the EPM persisting through day 28, than did unilateral MMI mice. Histological analysis confirmed bilateral microinfarcts and significant increase in Iba1- and GFAP-positive staining, indicating robust and sustained bilateral neuroinflammation.</div></div><div><h3>Conclusion</h3><div>This modified bilateral MMI procedure reproduces key pathological and functional features of human MID, overcoming the limitations of traditional unilateral models. The new model provides a clinically relevant platform for investigating mechanisms underlying vascular cognitive impairment and evaluating potential disease-modifying therapies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115598"},"PeriodicalIF":4.2,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780621","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}
Pub Date : 2025-12-15DOI: 10.1016/j.expneurol.2025.115594
Fan Wu , Yan Min , Zihan Xu , Luyuan Zhang, Lihui Zhou, Jianbo Yu, Ganglei Li, Hongwei Lin, Jie Shen, Zongchi Liu, Jian Shen, Renya Zhan, Jiangbiao Gong, Yu Zhu
Tremendous advances have been made in the understanding of neurogenesis in the adult brain, which offers hope for therapeutic strategies that target neurogenesis in the repair of nerve damage after stroke. Rac1 plays a key role in the neurogenesis of the central nervous system as one of the small GTPase members of the Rho family. However, the role of Rac1 after ischemic stroke remains controversial. This may be due to its role in mediated production of harmful substances such as ROS during the acute phase. Therefore, we are trying to explore whether it can play a role in nerve repair after the acute phase. Our research indicates that the activation of Rac1 in the post-acute phase supports ischemic recovery. Specifically, intraventricular injection of a Rac1 activator one week after middle cerebral artery occlusion (MACO) improved brain atrophy and neurological function. Rac1 activation induced the migration of neural stem cells in vitro and promoted their migration in vivo, aiding in their differentiation into mature neurons. Results from Western blotting and Co-immunoprecipitation (Co-IP) assaysuggest that Rac1 activation promotes the migration and differentiation of neural stem cells through the downstream Pak1/p38/β-catenin signaling pathway. Furthermore, Rac1 activation promotes post-stroke vascular regeneration and synaptic remodeling, In conclusion, the activation of Rac1 in the post-acute phase promotes neural repair following stroke, indicating its potential as a therapeutic target during the recovery phase of ischemic stroke.
{"title":"Post-acute phase Rac1 activation promotes long-term recovery of ischemic stroke via the Pak1/p38/β-catenin pathway","authors":"Fan Wu , Yan Min , Zihan Xu , Luyuan Zhang, Lihui Zhou, Jianbo Yu, Ganglei Li, Hongwei Lin, Jie Shen, Zongchi Liu, Jian Shen, Renya Zhan, Jiangbiao Gong, Yu Zhu","doi":"10.1016/j.expneurol.2025.115594","DOIUrl":"10.1016/j.expneurol.2025.115594","url":null,"abstract":"<div><div>Tremendous advances have been made in the understanding of neurogenesis in the adult brain, which offers hope for therapeutic strategies that target neurogenesis in the repair of nerve damage after stroke. Rac1 plays a key role in the neurogenesis of the central nervous system as one of the small GTPase members of the Rho family. However, the role of Rac1 after ischemic stroke remains controversial. This may be due to its role in mediated production of harmful substances such as ROS during the acute phase. Therefore, we are trying to explore whether it can play a role in nerve repair after the acute phase. Our research indicates that the activation of Rac1 in the post-acute phase supports ischemic recovery. Specifically, intraventricular injection of a Rac1 activator one week after middle cerebral artery occlusion (MACO) improved brain atrophy and neurological function. Rac1 activation induced the migration of neural stem cells in vitro and promoted their migration in vivo, aiding in their differentiation into mature neurons. Results from Western blotting and Co-immunoprecipitation (Co-IP) assaysuggest that Rac1 activation promotes the migration and differentiation of neural stem cells through the downstream Pak1/p38/β-catenin signaling pathway. Furthermore, Rac1 activation promotes post-stroke vascular regeneration and synaptic remodeling, In conclusion, the activation of Rac1 in the post-acute phase promotes neural repair following stroke, indicating its potential as a therapeutic target during the recovery phase of ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115594"},"PeriodicalIF":4.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774003","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}
Pub Date : 2025-12-14DOI: 10.1016/j.expneurol.2025.115589
Yizhen Weng , Jialei Zhou , Lulu Zhang , Xinyi He , Hui Guo , Quanquan Zhang , Haiying Li , Xiang Tang , Xiang Li Sr
Ischemic stroke often causes demyelination and cognitive impairment. Emerging evidence suggests that microRNAs regulate gene expression and influence myelin repair and cognitive recovery after stroke. Here, transcriptomic analysis and RT-qPCR validation revealed marked upregulation of miR-15b-5p expression in the hippocampal regions of MCAO/R rats. Similarly, elevated serum miR-15b-5p levels were observed in stroke patients and positively correlated with NIHSS scores and infarct volumes. Functional studies involving intracerebroventricular administration of miR-15b-5p agomirs or antagomirs revealed that inhibition of miR-15b-5p markedly enhanced cognitive performance and facilitated myelin repair, as demonstrated by immunofluorescence and transmission electron microscopy. In contrast, overexpression of miR-15b-5p through agomir administration aggravated cognitive impairments and demyelination. Mechanistically, E2F7 was identified as a direct target of miR-15b-5p via dual-luciferase reporter assays. Suppression of E2F7 led to increased expression of the pro-inflammatory chemokine CXCL2, thereby exacerbating neuroinflammation and demyelination. In contrast, inhibition of miR-15b-5p restored E2F7 expression and significantly reduced CXCL2 levels, as confirmed by Western blotting and enzyme-linked immunosorbent assay. Collectively, these findings reveal a novel miR-15b–E2F7–CXCL2 axis that modulates myelin repair and cognitive recovery after ischemic stroke, highlighting miR-15b-5p as a potential therapeutic target.
{"title":"miR-15b-5p impairs myelin repair and cognitive recovery after ischemic stroke by targeting the E2F7/CXCL2 axis","authors":"Yizhen Weng , Jialei Zhou , Lulu Zhang , Xinyi He , Hui Guo , Quanquan Zhang , Haiying Li , Xiang Tang , Xiang Li Sr","doi":"10.1016/j.expneurol.2025.115589","DOIUrl":"10.1016/j.expneurol.2025.115589","url":null,"abstract":"<div><div>Ischemic stroke often causes demyelination and cognitive impairment. Emerging evidence suggests that microRNAs regulate gene expression and influence myelin repair and cognitive recovery after stroke. Here, transcriptomic analysis and RT-qPCR validation revealed marked upregulation of miR-15b-5p expression in the hippocampal regions of MCAO/R rats. Similarly, elevated serum miR-15b-5p levels were observed in stroke patients and positively correlated with NIHSS scores and infarct volumes. Functional studies involving intracerebroventricular administration of miR-15b-5p agomirs or antagomirs revealed that inhibition of miR-15b-5p markedly enhanced cognitive performance and facilitated myelin repair, as demonstrated by immunofluorescence and transmission electron microscopy. In contrast, overexpression of miR-15b-5p through agomir administration aggravated cognitive impairments and demyelination. Mechanistically, E2F7 was identified as a direct target of miR-15b-5p via dual-luciferase reporter assays. Suppression of E2F7 led to increased expression of the pro-inflammatory chemokine CXCL2, thereby exacerbating neuroinflammation and demyelination. In contrast, inhibition of miR-15b-5p restored E2F7 expression and significantly reduced CXCL2 levels, as confirmed by Western blotting and enzyme-linked immunosorbent assay. Collectively, these findings reveal a novel miR-15b–E2F7–CXCL2 axis that modulates myelin repair and cognitive recovery after ischemic stroke, highlighting miR-15b-5p as a potential therapeutic target.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115589"},"PeriodicalIF":4.2,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767674","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}
Pub Date : 2025-12-13DOI: 10.1016/j.expneurol.2025.115596
Xu Li , Yuxiang Zhou , Yang Han , Xun Chen , Qian Ouyang
Hydrocephalus is characterized by the abnormal accumulation of cerebrospinal fluid (CSF) within the brain's ventricular system, which can lead to ventricular dilation. This condition affects individuals across all age groups but is particularly prevalent in infants and the elderly. The etiology of hydrocephalus is multifactorial, involving excessive CSF secretion, obstruction of CSF pathways, and impairment of CSF reabsorption. Recent evidence supports the CSF permeation theory, which emphasizes the exchange of CSF with blood and interstitial fluid throughout the brain, mediated by perivascular spaces, astrocytes, and brain parenchyma. This review focuses on the role and interactions of various cell types in CSF circulation and the development of hydrocephalus, including choroid plexus cells, choroid plexus macrophages, vascular endothelial cells, neural progenitor cells, perivascular macrophages, mast cells, astrocytes, ependymal cells, and meningeal lymphatic endothelial cells(mLECs). We discuss the mechanisms by which these cells contribute to hydrocephalus, such as the disruption of blood-CSF-barrier integrity, inflammation, and alterations in CSF dynamics. Additionally, we explore potential therapeutic strategies targeting these cellular interactions, such as the inhibition of chemokine signaling and the modulation of complement pathways. Understanding the complex interplay between different cell types is crucial for developing novel treatments for hydrocephalus. This review provides a comprehensive overview of the current knowledge regarding cellular contributions to hydrocephalus and highlights areas for future research.
{"title":"Cellular insights into hydrocephalus: The diverse roles and intricate crosstalk of multiple cell types","authors":"Xu Li , Yuxiang Zhou , Yang Han , Xun Chen , Qian Ouyang","doi":"10.1016/j.expneurol.2025.115596","DOIUrl":"10.1016/j.expneurol.2025.115596","url":null,"abstract":"<div><div>Hydrocephalus is characterized by the abnormal accumulation of cerebrospinal fluid (CSF) within the brain's ventricular system, which can lead to ventricular dilation. This condition affects individuals across all age groups but is particularly prevalent in infants and the elderly. The etiology of hydrocephalus is multifactorial, involving excessive CSF secretion, obstruction of CSF pathways, and impairment of CSF reabsorption. Recent evidence supports the CSF permeation theory, which emphasizes the exchange of CSF with blood and interstitial fluid throughout the brain, mediated by perivascular spaces, astrocytes, and brain parenchyma. This review focuses on the role and interactions of various cell types in CSF circulation and the development of hydrocephalus, including choroid plexus cells, choroid plexus macrophages, vascular endothelial cells, neural progenitor cells, perivascular macrophages, mast cells, astrocytes, ependymal cells, and meningeal lymphatic endothelial cells(mLECs). We discuss the mechanisms by which these cells contribute to hydrocephalus, such as the disruption of blood-CSF-barrier integrity, inflammation, and alterations in CSF dynamics. Additionally, we explore potential therapeutic strategies targeting these cellular interactions, such as the inhibition of chemokine signaling and the modulation of complement pathways. Understanding the complex interplay between different cell types is crucial for developing novel treatments for hydrocephalus. This review provides a comprehensive overview of the current knowledge regarding cellular contributions to hydrocephalus and highlights areas for future research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115596"},"PeriodicalIF":4.2,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755662","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}
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