Journal of Neurochemistry最新文献

{"title":"The Glutamate/GABA-Glutamine Cycle: Insights, Updates, and Advances","authors":"Jens V. Andersen","doi":"10.1111/jnc.70029","DOIUrl":"https://doi.org/10.1111/jnc.70029","url":null,"abstract":"<p>Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons and astrocytes known as the glutamate/GABA-glutamine cycle. In this cycle, astrocytes take up glutamate and GABA from the synapse and convert these neurotransmitters into glutamine. Astrocytic glutamine is subsequently transferred to neurons, serving as the principal precursor for neuronal glutamate and GABA synthesis. The glutamate/GABA-glutamine cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, and metabolism. All of these processes are deeply interdependent and closely coupled to cellular energy metabolism. Astrocytes display highly active mitochondrial oxidative metabolism and several unique metabolic features, including glycogen storage and pyruvate carboxylation, which are essential to sustain continuous glutamine release. However, new roles of oligodendrocytes and microglia in neurotransmitter recycling are emerging. Malfunction of the glutamate/GABA-glutamine cycle can lead to severe synaptic disruptions and may be implicated in several brain diseases. Here, I review central aspects and recent advances of the glutamate/GABA-glutamine cycle to highlight how the cycle is functionally connected to critical brain functions and metabolism. First, an overview of glutamate, GABA, and glutamine transport is provided in relation to neurotransmitter recycling. Then, central metabolic aspects of the glutamate/GABA-glutamine cycle are reviewed, with a special emphasis on the critical metabolic roles of glial cells. Finally, I discuss how aberrant neurotransmitter recycling is linked to neurodegeneration and disease, focusing on astrocyte metabolic dysfunction and brain lipid homeostasis as emerging pathological mechanisms. Instead of viewing the glutamate/GABA-glutamine cycle as individual biochemical processes, a more holistic and integrative approach is needed to advance our understanding of how neurotransmitter recycling modulates brain function in both health and disease.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595333","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":"Proteolysis-Based Biomarker Repertoire of the Neurofilament Proteome","authors":"Axel Petzold","doi":"10.1111/jnc.70023","DOIUrl":"https://doi.org/10.1111/jnc.70023","url":null,"abstract":"<p>Neurodegeneration presents a significant challenge in ageing populations, often being detected too late for effective intervention. Biomarkers have shown great potential in addressing this issue, with neurofilament (Nf) proteins emerging as validated biomarkers presently transitioning from research to routine laboratory use. Whilst advances in large-scale quantitative analyses have enabled the targeted study of proteolytic Nf fragments in blood, the complete landscape of the Nf proteolytic breakdown remains unknown. This study presents a comprehensive atlas of the human Nf isoform (<i>Z</i>) degradome, based on the number of known cleavage sites (<i>x</i>). The full scale of the Nf degradome is described by the formula: <i>Z</i> = ((<i>x</i> + 1) × (<i>x</i> + 2)/2) − 1. The resulting neurofilament degradome atlas (NDA) was validated through a triple-layer approach using in vitro data (open access at: https://doi.org/10.5522/04/25689378.v1). The NDA offers valuable applications in biomarker detection, targeted antibody development, exploration of autoimmunity and understanding Nf aggregate formation. Analysis of the Nf degradome reveals novel insights into neurodegenerative diseases by investigating peptide pools affected by genetic mutations in the Nf genome and alterations in proteolytic pathways. The annotated NDA is publicly available as a database resource, supporting advancements in affinity-based biomarker tests through informed peptide selection and minimising biases in label-free approaches. In conclusion, this study highlights the biological significance of a dynamic pool of coexisting proteolytic Nf peptides, providing a framework that can be applied to other proteins.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595334","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":"Surgical Stress and Non-Surgery Related Stress Synergistically Trigger Meningeal CD8+ T Cells Accumulation and Subsequent Brain Dysfunction in Mice","authors":"Shanqing Xu,&nbsp;Hui Chen,&nbsp;Aihua Tan,&nbsp;Hui Yang,&nbsp;Jianbin Tong","doi":"10.1111/jnc.70043","DOIUrl":"https://doi.org/10.1111/jnc.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>Patients are usually highly stressed during the immediate perioperative period. It remains unclear whether increased stress contributes to postoperative brain dysfunction. Here, the clinical perioperative setting was mimicked via exploratory laparotomy and perioperative restraint stress. The stress response was assessed by measuring the levels of stress hormones and IL-6 in peripheral blood. Behaviors were evaluated with the open field, novel object recognition, and Barnes maze tests. We found that surgical stress and non-surgery-related stress synergistically trigger meningeal CD8⁺T cell accumulation, brain dysfunction, and increased stress hormone and IL-6 levels in the peripheral blood of adult mice, but simple surgical stress or non-surgery-related stress had no significant effect on these parameters. Limiting meningeal CD8⁺ T cell accumulation with an anti-CD8 antibody alleviated the impact of surgery plus perioperative stress on brain function, neuroinflammation, and neurogenesis. The partial elimination of microglia before surgery alleviated postoperative meningeal CD8⁺ T cell accumulation, cognitive dysfunction, and decreased hippocampal chemotactic factor levels. Our findings indicate that the synergistic effect of surgical stress and non-surgery-related stress contributes to postoperative brain dysfunction by triggering meningeal CD8⁺ T cell accumulation, suggesting the potential of limiting non-surgery-related stress as a preventive method for postoperative brain dysfunction.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Investigation of Brain and Spinal Cord Pericytes After Inducible PDGFRβ+ Cell Ablation in Adult Mice","authors":"Dila Atak,&nbsp;Erdost Yıldız,&nbsp;Esra Özkan,&nbsp;Mohammadreza Yousefi,&nbsp;Ayşe Özkan,&nbsp;Aysu Bilge Yılmaz,&nbsp;Ali Burak Kızılırmak,&nbsp;Iman Asaad Alnajjar,&nbsp;Çiçek Kanar,&nbsp;Zeynep Lal Caan,&nbsp;Şakir Ümit Zeybek,&nbsp;Cem İsmail Küçükali,&nbsp;Erdem Tüzün,&nbsp;Yasemin Gürsoy-Özdemir,&nbsp;Atay Vural","doi":"10.1111/jnc.70035","DOIUrl":"https://doi.org/10.1111/jnc.70035","url":null,"abstract":"<p>Central nervous system (CNS) pericytes play crucial roles in vascular development and blood–brain barrier maturation during prenatal development, as well as in regulating cerebral blood flow in adults. They have also been implicated in the pathogenesis of numerous neurological disorders. However, the behavior of pericytes in the adult brain after injury remains poorly understood, partly due to limitations in existing pericyte ablation models. To investigate pericyte responses following acute ablation and characterize a novel rodent model for pericyte research, we developed a tamoxifen-inducible PDGFRβ⁺ cell ablation model by crossing <i>PDGFRβ-P2A-CreER</i>^<i>T2</i> and <i>Rosa26-DTA176</i> transgenic mouse lines. Using this model, we studied the effects of different tamoxifen doses and conducted histological examinations 15 and 60 days post-injection to assess the impacts of PDGFRβ⁺ cell ablation in both acute and chronic phases, respectively. Our results demonstrate that a low dose of tamoxifen effectively ablates PDGFRβ⁺ cells of the CNS in mice without reducing survival or causing significant systemic side effects, such as weight loss. Additionally, we found that the extent of PDGFRβ⁺ cell depletion varies between the cortex and the spinal cord, as well as between the gray and white matter regions of the spinal cord. Importantly, we observed that both pericyte coverage and numbers increased in the weeks following acute ablation, indicating the regenerative capacity of CNS pericytes in vivo. This study offers a valuable tool for future studies on the role of pericytes in neurological disorders by overcoming the limitations of constitutive pericyte ablation models and providing its longitudinal characterization in the CNS.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595076","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":"Therapeutic Treatment With OLX-07010 Inhibited Tau Aggregation and Ameliorated Motor Deficits in an Aged Mouse Model of Tauopathy","authors":"E. J. Davidowitz,&nbsp;P. Lopez,&nbsp;D. Patel,&nbsp;H. Jimenez,&nbsp;A. Wolin,&nbsp;J. Eun,&nbsp;L. Adrien,&nbsp;J. Koppel,&nbsp;D. Morgan,&nbsp;P. Davies,&nbsp;J. G. Moe","doi":"10.1111/jnc.70025","DOIUrl":"https://doi.org/10.1111/jnc.70025","url":null,"abstract":"<p>Targeting tau protein is a strategy for the development of disease-modifying therapeutics for Alzheimer's disease (AD) and numerous rare tauopathies. A small molecule approach targeting tau aggregation was used to select and optimize compounds inhibiting tau self-association in vitro that have translated in vivo in preventive studies in htau and P301L tau JNPL3 mouse models of tauopathy. In this therapeutic treatment study, aged JNPL3 mice with pre-existing tau aggregates were used to evaluate the therapeutic effect of OLX-07010. The study had a Baseline group of mice aged 7 months, a vehicle, and two dose groups treated until 12 months by administration in feed. The primary endpoint of the study was the reduction of insoluble tau aggregates with statistical significance. The secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of soluble tau, and improvement of motor behavior. ELISAs and immunoblots were used to determine the levels of tau and its aggregated forms including self-associated tau and Sarkosyl insoluble tau. Effect on motor behavior, as measured by Rotarod assay, was also assessed between the treatment groups. At the end of treatment, reduced levels of self-associated tau, Sarkosyl insoluble tau aggregates, and overall levels of tau in the heat-stable fraction with statistical significance in the cortex were observed. Treatment prevented the accumulation of tau aggregates above baseline, and in parallel, treatment groups had improved motor behavior in a Rotarod assay compared to baseline and vehicle control groups, suggesting that treatment was rescuing motor impairment in aged mice. The functional and biochemical readouts suggest that this small molecule has potential for treating neurodegenerative diseases characterized by tau aggregation such as AD and progressive supranuclear palsy.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564932","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":"Exploring the Structural Dynamics of LeuT Using EPR Spectroscopy: A Focus on Transmembrane Helix 10","authors":"Petros Tsalagradas,&nbsp;Callum Eke,&nbsp;Courtney Andrews,&nbsp;Fraser MacMillan","doi":"10.1111/jnc.70034","DOIUrl":"https://doi.org/10.1111/jnc.70034","url":null,"abstract":"<p>The amino-acid transporter LeuT from <i>Aquifex aeolicus</i> is a well-studied bacterial homologue of the neurotransmitter: sodium symporters (NSS), especially the solute carrier 6 (SLC6) family. Within the nervous system, SLC6 transporters play a vital role in the termination of synaptic transmission, and their dysfunction leads to severe neurological conditions, rendering them key pharmacological targets. LeuT was the first SLC6 homologue to be crystallised and remains the main reference transporter to develop transport cycle models for its eukaryotic counterparts. Here, we aim to probe LeuT and investigate mechanistically important conformational changes using a combination of Site-Directed Spin Labelling (SDSL) and Electron Paramagnetic Resonance (EPR) spectroscopic techniques in detergent solubilised micelles and proteoliposomes. We focus, primarily, on ‘subtle’ structural, molecular motions occurring at the extracellular region of transmembrane helix (TM) 10, which cannot be resolved using conventional high-resolution crystallographic techniques. We observe similar but not identical ion/ligand-dependent conformational changes of LeuT on the extracellular domain of TM10 in detergent micelles and proteoliposomes. Close agreement is also observed between <i>in silico</i> analysis of existing static structural models and the experimental data acquired here in the form of coarse-grained accessibility restraints, demonstrating that such subtle movements can be important for understanding both function and mechanism. The observed differences for the dynamics of LeuT in different environments underpin future work, which aims to explore ‘more native’ reconstituted proteoliposome conditions more thoroughly using pulsed EPR methods before generalised conclusions can be drawn on the physiological relevance of such structural changes and whether they can provide novel insights on the molecular events underlying the transport cycle of LeuT.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564927","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":"A Viral Labelling Study of Spinal Trigeminal Nucleus Caudalis Projection Neurons Targeting the Parabrachial Nucleus","authors":"Sophie Maric,&nbsp;Mehedi Hasan,&nbsp;Madison L. Pounder,&nbsp;Brett A. Graham,&nbsp;Tyler J. Browne","doi":"10.1111/jnc.70028","DOIUrl":"https://doi.org/10.1111/jnc.70028","url":null,"abstract":"<p>Projection neurons (PNs) in the Spinal Trigeminal Nucleus Caudalis (Sp5C) relay orofacial nociceptive information to higher brain regions such as the thalamus and the parabrachial nucleus (PBN). Our understanding of Sp5C PN organisation and function has advanced less than the parallel spinal cord output system despite their corresponding roles for transmission of nociceptive signals from the orofacial region and body respectively. Viral vectors are an established approach for studying circuit connectivity in the nervous system, but different serotypes are known to produce variable results across circuits. As such, we sought to validate the utility of two common viral serotypes in spinal PN research: retrograde adeno-associated virus serotype 2 (rgAAV) and adeno-associated virus serotype 9 (AAV9), for identifying and analysing Sp5C PNs that project to the PBN. Following unilateral injections of either viral serotype into the PBN, many Sp5C projection neurons were retrogradely labelled. For both serotypes, these injections labelled Sp5C PNs bilaterally with a strong bias to the ipsilateral Sp5C. Within Sp5C, similar levels of PN labelling were present in both superficial and deep regions, contrasting previous work in spinal PNs that showed greater labelling by AAV9 versus rgAAV. Comparisons of the age dependence of labelling showed greater retrograde labelling of Sp5C projection neurons when injections were made in young adult animals. Finally, we demonstrate successful Cre-dependent recombination to selectively express channelrhodopsin-2 in Sp5C projection neurons. Together, these experiments show that rgAAV and AAV9 produce strong Sp5C PN transduction and provide a basis for future study of the afferent and efferent functions of the Sp5C PN population in health and disease.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564828","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":"Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure","authors":"Seong-Hun Bong,&nbsp;Hayoung Choi,&nbsp;Hyun-Ho Song,&nbsp;Dong Kyu Kim,&nbsp;Inhee Mook-Jung,&nbsp;Do Yup Lee","doi":"10.1111/jnc.70030","DOIUrl":"https://doi.org/10.1111/jnc.70030","url":null,"abstract":"<div>\u0000 \u0000 <p>Microglia, key immune cells in the brain, play a pivotal role in brain homeostasis and immune responses. Emerging evidence suggests their critical involvement in Alzheimer's disease (AD) pathogenesis and propagation. The propagation of AD pathology is related to the extracellular matrix of microglia, including extracellular vesicles (EV). Recently, microglia-derived EVs are implicated in inflammatory processes and neuronal death. This study aimed to extensively profile and propose the metabolic role of microglial EVs in AD. Accordingly, we determined the significant alterations of the EV metabolome associated with the metabolites in primary microglial cells. Aβ exposure induced significant metabolic alteration of 39, 18, and 28 metabolites in microglial cells, cultured media, and EVs, respectively. Aβ exposure triggered common alteration of key metabolic pathways between microglial cells and EVs, including purine, amino acid, and fatty acid metabolisms. While most of the common metabolites showed the same directional changes among the microglial system, <i>N</i>-acetyl aspartic acid displayed the opposite directional change in EVs. <i>N</i>-acetyl aspartic acid decreased 2.3-fold and twofold in microglial cells and media, respectively, but increased 3.5-fold in EVs under Aβ exposure. Moreover, mediation analysis proposed key EV metabolites that were directly affected by the metabolic dysregulation of Aβ-exposed microglial cells. The up-regulation of cysteic acid in EVs was mediated by up-regulated IMP in microglial cells. The down-regulation of 1–16:0-lysoPE in EVs was mediated by stearoyl-L-carnitine in microglial cells. Our study sheds new light on the role of microglia and EVs in neurodegenerative diseases, offering promising avenues for future therapeutic interventions.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of Cathepsin S Expression Contributes to Neuronal Damage Following Kainic Acid–Induced Status Epilepticus","authors":"Hsin-Ling Shih,&nbsp;Kuan-Hsiang Cheng,&nbsp;Chin-Hao Chen,&nbsp;Jang-Yang Chang,&nbsp;Kuei-Sen Hsu","doi":"10.1111/jnc.70037","DOIUrl":"https://doi.org/10.1111/jnc.70037","url":null,"abstract":"<div>\u0000 \u0000 <p>Status epilepticus (SE) is a life-threatening neurological emergency characterized by persistent seizures, leading to brain damage that increases the risk of recurrent seizures due to abnormal electrical impulses produced by damaged neurons. However, the molecular mechanism by which convulsive SE leads to neuronal damage is not completely understood. Cathepsin S (Ctss), a lysosomal cysteine protease, has been implicated in secondary injury after traumatic brain injury. This study sought to explore whether Ctss is also involved in SE-induced neuronal damage in the hippocampus. Immunohistochemistry and Western blotting were utilized to detect the expression of Ctss in the hippocampal subregions of male C57BL/6J mice at various times following kainic acid (KA)–induced SE. The reactivity of microglia was assessed using immunohistochemistry, and Fluoro-Jade C (FJC) staining was employed to identify damaged neurons. We found that the mature form of Ctss is barely observed in naïve adult (12-week-old) mouse hippocampus, but its expression is significantly evident at 50 weeks of age. In adult mice, the expression of both pro-and mature forms of Ctss in the hippocampal CA3 region was increased as early as 16 h following KA-induced SE. The increased Ctss immunoreactivity was mainly found in microglia following KA-induced SE. The damaged neurons visualized by FJC staining were prominent in the CA3 region at 16 h following KA-induced SE. <i>Ctss</i> knockdown did not affect KA-induced behavioral seizures but significantly reduced SE-induced microglia activation and neuronal damage. An increase in chemokine CX3C motif ligand 1 (CX3CL1) immunoreactivity on microglia was observed following KA-induced SE, and CX3C motif chemokine receptor 1 (CX3CR1) antagonist AZD8797 treatment significantly attenuated SE-induced microglia activation and neuronal damage. Altogether, these results indicate a crucial role of Ctss in SE-induced neuronal damage, possibly through CXC3L1-mediated microglial activation, and provide a new perspective for preventing SE-induced neuronal damage.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Non-Coding RNA Regulation of the Blood–Brain Barrier in Neurodegenerative Diseases: A Systematic Review","authors":"Mohamed Maazouzi,&nbsp;Madiha Rasheed,&nbsp;Lamia Mbarek,&nbsp;Xuezhe Wang,&nbsp;Junhan Liang,&nbsp;Hong Ma,&nbsp;Zixuan Chen,&nbsp;Yulin Deng","doi":"10.1111/jnc.70031","DOIUrl":"https://doi.org/10.1111/jnc.70031","url":null,"abstract":"<p>Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and dysfunction, leading to significant cognitive and motor impairments. The disruption of the blood–brain barrier (BBB) integrity, a key regulator of central nervous system homeostasis, emerges as a critical factor in the pathogenesis of these disorders. Accumulating evidence implicates non-coding RNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in BBB regulation. However, the intricate network governing BBB dysfunction and consequent neurodegeneration remains obscure. This systematic review maps the convergent microRNA networks in Alzheimer's, Parkinson's, and multiple sclerosis, unveiling their putative roles in BBB modulation. We analyzed data from 11 peer-reviewed clinical studies, identifying key miRNAs such as hsa-miR-155, hsa-miR-22, hsa-miR-146a, hsa-miR-100-3p, and hsa-miR-182-5p as critical regulators of BBB permeability and inflammatory responses. Enrichment analysis revealed that these miRNAs modulate pathways related to inflammation, oxidative stress, and neuronal survival. Our review also uncovered extensive interactions between these miRNAs and transcription factors like JUN, RELA, STAT3, and TP53, as well as lncRNAs such as MALAT1, NEAT1, NORAD, and SNHG16. These interactions highlight complex regulatory networks involving miRNA sponging and chromatin remodeling, which may play crucial roles in maintaining BBB integrity. These analyses underscore the importance of miRNA-mediated regulatory networks in BBB function and offer insights into potential therapeutic targets for NDs.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535794","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}