Frontiers in Cellular Neuroscience最新文献

{"title":"APOE genotype-dependent differences in human astrocytic energy metabolism.","authors":"Vanessa Budny, Chantal Bodenmann, Kathrin J Zürcher, Maik Krüger, Sherida M de Leeuw, Rebecca Z Weber, Ruslan Rust, Luca Ravotto, Iván Ruminot, L Felipe Barros, Bruno Weber, Christian Tackenberg","doi":"10.3389/fncel.2025.1603657","DOIUrl":"10.3389/fncel.2025.1603657","url":null,"abstract":"<p><strong>Introduction: </strong>The main genetic risk factor for Alzheimer's disease (AD) is the presence of the apolipoprotein E4 (<i>APOE4</i>) allele. While <i>APOE4</i> increases the risk of developing AD, the <i>APOE2</i> allele is protective and <i>APOE3</i> is risk-neutral. In the brain, APOE is primarily expressed by astrocytes and plays a key role in various processes including cholesterol and lipid transport, neuronal growth, synaptic plasticity, immune response and energy metabolism. Disruptions in brain energy metabolism are considered a major contributor to AD pathophysiology, raising a key question about how different APOE isoforms affect the energy metabolism of human astrocytes.</p><p><strong>Methods: </strong>In this study, we generated astrocytes (iAstrocytes) from <i>APOE</i>-isogenic human induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE knockout (<i>APOE-KO</i>), and investigated <i>APOE</i> genotype-dependent changes in energy metabolism.</p><p><strong>Results: </strong>ATP Seahorse assay revealed a reduced mitochondrial and glycolytic ATP production in <i>APOE4</i> iAstrocytes. In contrast, glycolysis stress tests demonstrated enhanced glycolysis and glycolytic capacity in <i>APOE4</i> iAstrocytes while genetically encoded nanosensor-based FLIM analysis revealed that <i>APOE</i> does not affect lactate dynamics. In agreement with the increased glycolytic activity, <i>APOE4</i> iAstrocytes also showed elevated mitochondrial respiration and activity, indicated by proteomic GO enrichment analysis and mitochondrial stress test. This was accompanied by elevated proton leak in <i>APOE4</i> iAstrocytes while levels of mitochondrial uncoupling proteins (UCPs) were not affected. Mass spectrometry-based metabolomic analysis identified various energy and glucose metabolism-related pathways that were differentially regulated in <i>APOE4</i> compared to the other genotypes, including mitochondrial electron transport chain (ETC) and glycolysis. In general, <i>APOE2</i> and <i>APOE-KO</i> iAstrocytes showed a very similar phenotype in all functional assays and differences between <i>APOE2</i>/<i>APOE-KO</i> and <i>APOE4</i> were stronger than between <i>APOE3</i> and <i>APOE4</i>.</p><p><strong>Discussion: </strong>Our study provides evidence for <i>APOE</i> genotype-dependent effects on astrocyte energy metabolism and highlights alterations in the bioenergetic processes of the brain as important pathomechanisms in AD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1603657"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NcRNAs: a potential treatment for spinal cord injury.","authors":"Jie Bao, Wenhui Zhi, Sheng Qi, Haolong Mo, Ruzhuan Liu, Chunhui Guo","doi":"10.3389/fncel.2025.1645639","DOIUrl":"10.3389/fncel.2025.1645639","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a serious disorder that affects sensory, motor, and autonomic functions. Its pathological process is divided into two stages: primary and secondary injury. The secondary injury involves a variety of biological cascade reactions, leading to an imbalance in the spinal cord microenvironment. Non-coding RNAs (ncRNAs) play a crucial regulatory role in the pathophysiological process of spinal cord injury, including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), all of which are involved in processes such as axonal regeneration, oxidative stress, inflammatory response, autophagy, and apoptosis. Although the pathophysiological process of spinal cord injury has been partially elucidated, its pathogenesis is not yet fully understood, and effective treatments are limited. This article reviews the regulatory role and molecular mechanisms of ncRNAs in the development and progression of spinal cord injury and proposes strategies for treating spinal cord injury by regulating ncRNAs.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1645639"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered miR-214 enriched Schwann cell-derived extracellular vesicles amplify therapeutic efficacy for peripheral neuropathy in T2D mice.","authors":"Lei Wang, Xuerong Lu, Alexandra Szalad, Yi Zhang, Yanfeng Li, Mei Lu, Amy Kemper, Zhongwu Liu, Xian Shuang Liu, Michael Chopp, Zheng Gang Zhang","doi":"10.3389/fncel.2025.1649830","DOIUrl":"10.3389/fncel.2025.1649830","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) derived from healthy Schwann cells (SC-EVs) ameliorate peripheral neuropathy in diabetic mice and rescue sciatic nerve function in Schwann cell Dicer knockout mice in part via SC-EV cargo miRNAs. Among these miRNAs, miR-214 repairs nerve damage. The present study investigated whether engineered SC-EVs with elevated miR-214 (214-EVs), further amplify the therapeutic effect of naïve SC-EVs (naïve-EVs) on reducing diabetic peripheral neuropathy (DPN) in a mouse model of high-fat diet (HFD)-streptozotocin (STZ) induced type 2 diabetes. Compared to naïve-EVs, 214-EVs significantly improved motor and sensory nerve conduction velocity of the sciatic nerve and thermal latency, which were associated with increased intraepidermal nerve fiber density, axonal diameter, and myelin thickness in the sciatic nerve. Quantitative RT-PCR and Western blot analyses of sciatic nerve tissues showed that, compared to naïve-EVs, 214-EVs significantly increased miR-214 levels and downregulated axonal inhibitory protein PTEN and the myelination inhibitory protein cJUN. Furthermore, 214-EVs markedly suppressed neuroinflammation by decreasing CD68 + macrophages and inactivating the TLR4/NF-κB signaling pathway. Collectively, our findings demonstrate that miR-214-enriched SC-EVs are superior to naïve-EVs to ameliorate DPN and represent a promising EV-based therapeutic strategy.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1649830"},"PeriodicalIF":4.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type-specific molecular signaling architectures and synaptic plasticity of <i>Drosophila</i> olfactory sensory neurons.","authors":"Namrata Acharya, Eric Wiesel, Mareike Selcho, Nadine Ehmann, Marius Lamberty, Bill S Hansson, Dieter Wicher, Robert J Kittel","doi":"10.3389/fncel.2025.1579821","DOIUrl":"10.3389/fncel.2025.1579821","url":null,"abstract":"<p><p>Olfactory sensory neurons (OSNs) detect odours at a wide range of intensities. In <i>Drosophila</i>, volatile compounds bind to specific odorant receptors (ORs), which tune the sensitivity of chemoreception. To test whether additional mechanisms underlie odour-specific neuronal processing, we analysed the spatial distribution of ORs in dendrites and investigated OSN synapses in the antennal lobe, the first relay station of the olfactory pathway. Here, we studied the molecular structure and plasticity of the presynaptic active zone (AZ), the specialized site of neurotransmitter release. We focused on a highly sensitive OSN type that expresses the receptor Or56a and is exclusively activated by geosmin, an odorant signalling ecologically harmful microorganisms. Our results uncover a differential arrangement of dendritic ORs and core AZ proteins in alarm odour-detecting Or56a compared to conventional food-odour detecting OSNs. Interestingly, the data also show that Or56a OSNs display a limited capacity for homeostatic plasticity in response to a genetic reduction of presynaptic release probability. We hypothesise that this feature reflects the basal tuning of geosmin-sensing neurons towards maximum levels of performance.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1579821"},"PeriodicalIF":4.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human brain organoids: an innovative model for neurological disorder research and therapy.","authors":"Hancheng Li, Junxiao Zhu, Jieyu Li, Yangkai Wu, Chaohua Luo, Yuting Huang, Jieru Wu, Wenhua Liu, Hongwu Wang, Zhixian Mo","doi":"10.3389/fncel.2025.1658074","DOIUrl":"10.3389/fncel.2025.1658074","url":null,"abstract":"<p><p>The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D <i>in vitro</i> neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1658074"},"PeriodicalIF":4.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinal progenitor cells (jCell) for retinitis pigmentosa.","authors":"Jing Yang, Baruch D Kuppermann, David Liao, Mitul C Mehta, Chinhui Hsiang, Steven Menges, David S Boyer, Henry Klassen","doi":"10.3389/fncel.2025.1646156","DOIUrl":"10.3389/fncel.2025.1646156","url":null,"abstract":"<p><strong>Objective: </strong>To assess the safety and tolerability of intravitreal injection of human retinal progenitor cells (RPCs) at multiple dose levels in adults with non-syndromic retinitis pigmentosa (RP).</p><p><strong>Design: </strong>A prospective, multicenter, open-label, single-arm, Phase I/IIa safety study of RPCs in adults with RP (<i>n</i> = 28). Two patient cohorts were studied: Cohort 1: BCVA no better than 20/200 and no worse than Hand Motions, and Cohort 2: BCVA no better than 20/40 and no worse than 20/200).</p><p><strong>Subjects: </strong>Adults (<i>n</i> = 28) with a clinical diagnosis of RP confirmed by electroretinogram, consenting to gene mutation typing for genes involved in inherited retinal degenerations and related disorders, and willing to undergo human leukocyte antigen (HLA) typing.</p><p><strong>Methods: </strong>Subjects, who were not selected for genotype, were divided across the two vision cohorts with each receiving a single intravitreal injection of one of: 0.5, 1.0, 2.0, or 3.0 × 10⁶ allogeneic RPCs. Initially, subjects received the lowest dose (0.5 × 10⁶ RPCs) in the worse-seeing eye. Each dose group contained equal numbers of subjects from Cohorts 1 and 2.</p><p><strong>Results: </strong>Intravitreal RPC injection was well tolerated and associated with mostly transient mild to moderate adverse events. There were no signs of graft rejection. While primarily a safety study, exploratory efficacy assessments suggested improved BCVA measurements at all doses, with a possible dose-response at the highest levels. Mean BCVA change from pre-treatment to Month 12 in the treated vs untreated eyes was 1.4 letters for the 0.5 × 10⁶ dose group, 1.0 letters for the 1.0 × 10⁶ group, 4.8 letters for the 2.0 × 10⁶ group, and 9.0 letters for the 3.0 × 10⁶ group. Additional patient-reported changes included increased light sensitivity, improved object recognition, color discrimination, and reading.</p><p><strong>Conclusion: </strong>A single intravitreal injection of RPCs was well tolerated in this safety study. The exploratory efficacy data suggest potential improvement of BCVA in some RP patients, particularly at the highest dose. While viewed cautiously, the possible treatment effect should be further investigated in larger controlled studies. The RPC technology has received FDA Regenerative Medicine Advanced Therapy designation. Later phase studies are ongoing.</p><p><strong>Clinical trial registration: </strong>https://clinicaltrials.gov/study/NCT02320812, NCT02320812.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1646156"},"PeriodicalIF":4.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The distinct effects of metformin and imeglimin on high glucose-induced alterations in metabolic function and reactive oxygen species production in mouse Schwann cells are modulated by pemafibrate and/or fatty acid-binding proteins.","authors":"Hiroshi Ohguro, Megumi Higashide, Nami Nishikiori, Toshifumi Ogawa, Masato Furuhashi, Tatsuya Sato, Megumi Watanabe","doi":"10.3389/fncel.2025.1634262","DOIUrl":"10.3389/fncel.2025.1634262","url":null,"abstract":"<p><strong>Background: </strong>Imeglimin (Ime), the first in a novel class of antidiabetic agents, has potential therapeutic effects on diabetic peripheral neuropathy (DPN). This study aimed to evaluate and compare the effects on cellular metabolic function and reactive oxygen species (ROS) levels in high glucose-treated mouse Schwann cells (SCs), an <i>in vitro</i> DPN model, with those of metformin (Met), a conventional antidiabetic agent known for its beneficial effects on DPN. The roles of PPARα and fatty acid-binding proteins 5 and 7 (FABP5 and FABP7), both of which have been implicated in the pathogenesis of DPN, were also investigated.</p><p><strong>Methods: </strong>Schwann cells were treated with high glucose, Ime, Met, a selective PPARα agonist pemafibrate (Pema), or a FABP5/FABP7 inhibitor (MF6). Cell viability assays, extracellular flux analysis, and ROS production assays were performed.</p><p><strong>Results: </strong>No significant changes in cell viability were observed with any treatment. High glucose exposure increased glycolytic reserve compared to normal glucose conditions. Ime increased mitochondrial respiratory functions, whereas Met suppressed mitochondrial respiration and enhanced glycolytic functions, with these effects being more evident under normal glucose conditions. Pema significantly increased basal glycolysis under high glucose conditions, while MF6 had no appreciable effect. Both Ime and Met reduced ROS production in high glucose-treated SCs, with Ime exhibiting a more potent effect. However, the ROS-reducing effects of Ime and Met were abolished by Pema or MF6.</p><p><strong>Conclusion: </strong>Imeglimin exerted beneficial biological effects by enhancing the energetic state and reducing ROS production without inducing metabolic quiescence in high glucose-treated SCs. These findings suggest that Ime has therapeutic potential for DPN, although its effects may be modulated by intracellular lipid metabolism.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1634262"},"PeriodicalIF":4.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CaMKII modulates memory destabilization by regulating the interaction of theta and gamma oscillations.","authors":"Janine I Rossato, Maria Carolina Gonzalez, Johseph P G Souza, Andressa Radiske, Gênedy Apolinario, Ana Luizi Baracho, Martín Cammarota","doi":"10.3389/fncel.2025.1620588","DOIUrl":"10.3389/fncel.2025.1620588","url":null,"abstract":"<p><p>Object recognition memory (ORM) allows animals to distinguish between novel and familiar items. When reactivated during recall in the presence of a novel object, a consolidated ORM can be destabilized and linked to that generated by the novel object through reconsolidation. The CA1 region of the dorsal hippocampus contributes to ORM destabilization and reconsolidation, with mechanisms involving theta/gamma cross-frequency coupling (hPAC) and synaptic plasticity modulation. Ca²+/calmodulin-dependent protein kinase II (CaMKII) is vital for hippocampus-dependent memory processing and has been associated with theta activity-dependent plasticity in dorsal CA1. However, the specific role of hippocampal CaMKII in the lasting storage of reactivated ORM remains unclear, and its potential impact on memory-related oscillatory activity has not been previously investigated. To explore these questions, we employed a combination of behavioral, electrophysiological, and pharmacological approaches at various stages of ORM processing, and found that CaMKII is not necessary for ORM recall or reconsolidation but does regulate novelty-induced ORM destabilization by modulating hPAC.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1620588"},"PeriodicalIF":4.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Buffering brain aging: education moderates language impairment in Parkinson's disease.","authors":"Minchul Kim, Kwangsun Yoo","doi":"10.3389/fncel.2025.1606451","DOIUrl":"10.3389/fncel.2025.1606451","url":null,"abstract":"<p><strong>Background: </strong>Cognitive reserve (CR) refers to the discrepancy between brain pathology and observed cognitive decline. While education is a key indicator of CR, its role as a potential moderator in the relationships between brain morphology and cognitive impairments in Parkinson's disease (PD) remains unclear. This study examined whether education affects the relationship between brain age and cognitive impairments in patients with PD.</p><p><strong>Methods: </strong>Data from 58 patients with PD were analyzed using a secondary dataset from the OpenNeuro database. Participants aged ≥55 years were on stable medications and underwent standardized neuropsychological assessments. Brain age predictions were generated from T1-weighted magnetic resonance imaging (MRI) using the brainageR package, and the brain age difference (BAD) was calculated after correction for regression dilution. The moderation effect of education on the relationship between BAD and cognition was assessed using Hayes' PROCESS macro. The primary outcome was cognitive performance across six domains: attention, executive function, language, learning and memory, visuospatial ability, and global cognition.</p><p><strong>Results: </strong>Among the six domains, a significant moderation effect of education was found only for language ability (β = 0.01, <i>p</i> = 0.013, <i>R</i> ² = 0.20). The relationship between BAD and language was steeper at lower education levels. No statistically significant moderation was found in the remaining five domains.</p><p><strong>Conclusion: </strong>Having more years of education is associated with buffering the effects of accelerated brain aging on language ability in PD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1606451"},"PeriodicalIF":4.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective effects of saikosaponin-A in ethanol-induced glia-mediated neuroinflammation, oxidative stress via RAGE/TLR4/NFkB signaling.","authors":"Waqar Ali, Kyonghwan Choe, Min Hwa Kang, Jawad Ali, Hyun Young Park, Abubakar Atiq, Sareer Ahmad, Tae Ju Park, Myeong Ok Kim","doi":"10.3389/fncel.2025.1625362","DOIUrl":"10.3389/fncel.2025.1625362","url":null,"abstract":"<p><p>Chronic use of ethanol leads to psychological and physiological dependence followed by neurodegeneration via glia-mediated neuroinflammation, and oxidative stress. The current study is aimed at the neuroprotective effects of saikosaponin-A against ethanol-induced neurodegeneration. Here, saikosaponin-A 10 mg/kg i.p., for 7 days was used against the ethanol (5 g/kg i.p., for 6 weeks) induced neuroinflammation via RAGE/TLR4 signaling in mouse neurodegenerative model. The immunoblotting and immunofluorescences microscopy results showed that, ethanol activates the glial cells at the level of mice brain. The relative expression of Toll like receptor (TLR4), receptor for advance glycation end product (RAGE), ionized calcium binding adaptor molecules 1 (Iba-1), glial fibrillary acidic protein (GFAP) was upregulated in ethanol-treated mice group. However, expression level of inflammatory biomarkers were downregulated in ethanol + SSA co-treated group. Similarly, our finding revealed that SSA significantly reduced the protein expression level of Phospo c-Jun N-Terminal Kinase (p-JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and downstream signaling targets in ethanol + SSA co-treated group. SSA also regulates the elevated ethanol-induced oxidative stress via NRF2 and HO-1 proteins. Finally, we analyzed the synaptic and behavioral alteration that was reversed in SSA treated group. Taken together, we concluded that SSA exhibits anti-inflammatory and antioxidant effects against ethanol-induced neurodegeneration.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1625362"},"PeriodicalIF":4.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}