Pub Date : 2024-10-30eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1464595
Ke Xu, Yu Zhang, Yue Shi, Yake Zhang, Chengguang Zhang, Tianjiao Wang, Peizhu Lv, Yan Bai, Shun Wang
Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), abnormal accumulation of α-synuclein (α-syn), and activation of microglia leading to neuroinflammation. Disturbances in circadian rhythm play a significant role in PD, with most non-motor symptoms associated with disruptions in circadian rhythm. These disturbances can be observed years before motor symptoms appear and are marked by the emergence of non-motor symptoms related to PD, such as rapid eye movement sleep behavior disorder (RBD), restless leg syndrome (RLS), excessive daytime sleepiness (EDS), depression and anxiety, changes in blood pressure, gastrointestinal dysfunction, and urinary problems. Circadian rhythm disruption precedes the onset of motor symptoms and contributes to the progression of PD. In brief, this article outlines the role of circadian rhythm disruption in triggering PD at cellular and molecular levels, as well as its clinical manifestations. It also explores how circadian rhythm research can contribute to preventing the onset and progression of PD from current and future perspectives.
帕金森病(Parkinson's disease,PD)是一种神经退行性疾病,其特征是神经黑质(substantia nigra pars compacta,SNpc)中多巴胺能神经元的逐渐丧失、α-突触核蛋白(α-syn)的异常积累以及小胶质细胞的激活导致神经炎症。昼夜节律紊乱在帕金森病中起着重要作用,大多数非运动症状都与昼夜节律紊乱有关。这些紊乱可在运动症状出现前数年被观察到,其特征是出现与帕金森病有关的非运动症状,如快速眼动睡眠行为障碍(RBD)、不宁腿综合征(RLS)、白天过度嗜睡(EDS)、抑郁和焦虑、血压变化、胃肠功能紊乱和泌尿系统问题。昼夜节律紊乱先于运动症状出现,并导致帕金森病的进展。本文简要概述了昼夜节律紊乱在细胞和分子水平上引发帕金森病的作用及其临床表现。文章还从当前和未来的角度探讨了昼夜节律研究如何有助于预防帕金森病的发生和发展。
{"title":"Circadian rhythm disruption: a potential trigger in Parkinson's disease pathogenesis.","authors":"Ke Xu, Yu Zhang, Yue Shi, Yake Zhang, Chengguang Zhang, Tianjiao Wang, Peizhu Lv, Yan Bai, Shun Wang","doi":"10.3389/fncel.2024.1464595","DOIUrl":"10.3389/fncel.2024.1464595","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), abnormal accumulation of α-synuclein (α-syn), and activation of microglia leading to neuroinflammation. Disturbances in circadian rhythm play a significant role in PD, with most non-motor symptoms associated with disruptions in circadian rhythm. These disturbances can be observed years before motor symptoms appear and are marked by the emergence of non-motor symptoms related to PD, such as rapid eye movement sleep behavior disorder (RBD), restless leg syndrome (RLS), excessive daytime sleepiness (EDS), depression and anxiety, changes in blood pressure, gastrointestinal dysfunction, and urinary problems. Circadian rhythm disruption precedes the onset of motor symptoms and contributes to the progression of PD. In brief, this article outlines the role of circadian rhythm disruption in triggering PD at cellular and molecular levels, as well as its clinical manifestations. It also explores how circadian rhythm research can contribute to preventing the onset and progression of PD from current and future perspectives.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1464595"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617608","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}
Pub Date : 2024-10-30eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1471005
Wenqiang Quan, Yann Decker, Qinghua Luo, Axel Chemla, Hsin-Fang Chang, Dong Li, Klaus Fassbender, Yang Liu
Introduction: Activation of NLRP3-containing inflammasome, which is responsible for IL-1β maturation, has been shown to contribute to Alzheimer's disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown.
Methods: NLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and Nlrp3 knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of Nlrp3 knockout and wild-type mice were cultured, treated with IL-1β and H2O2 at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ antibody.
Results: Deficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated Osteopontin gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H2O2 increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner.
Discussion: Inhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer's patients.
导言:含NLRP3的炎性体负责IL-1β的成熟,在APP和tau转基因小鼠中,NLRP3炎性体的激活已被证明有助于阿尔茨海默病(AD)相关的发病机制。然而,NLRP3对AD的周细胞和随后的脑血管病变的影响仍然未知:方法:通过将人类 P301S tau 转基因小鼠和 Nlrp3 基因敲除小鼠杂交,产生了 NLRP3 缺失型和野生型 AD 动物模型。采用免疫组织学和分子生物学方法研究了与AD相关的神经炎症、tau病变、脑血管和周细胞覆盖。为了研究NLRP3如何调控周细胞的活化和存活,研究人员培养了Nlrp3基因敲除小鼠和野生型小鼠大脑中的周细胞,用不同浓度的IL-1β和H2O2处理,并用荧光标记的类磷脂酰蛋白、annexin-V和PDGFRβ抗体染色后,用共聚焦显微镜和流式细胞术进行分析:结果:NLRP3的缺失(1)减少了Iba-1、GFAP和AT8抗体免疫反应的磷酸化tau阳性细胞,而没有显著改变炎症基因的转录;(2)保护了脑血管和周细胞覆盖,并上调了Osteopontin基因的转录;(3)改善了tau转基因小鼠的认知功能。在细胞培养中,NLRP3 的缺乏可防止周细胞凋亡。用IL-1β或H2O2处理可增加NLRP3缺陷型周细胞中PDGFRβ的表达,但在NLRP3野生型周细胞中,PDGFRβ的表达则以剂量依赖的方式减少:讨论:抑制NLRP3可促进周细胞存活,改善脑血管功能,减轻tau转基因小鼠脑内的AD病理变化。我们的研究支持将 NLRP3 作为阿尔茨海默病患者的新型治疗靶点。
{"title":"Deficiency of NLRP3 protects cerebral pericytes and attenuates Alzheimer's pathology in tau-transgenic mice.","authors":"Wenqiang Quan, Yann Decker, Qinghua Luo, Axel Chemla, Hsin-Fang Chang, Dong Li, Klaus Fassbender, Yang Liu","doi":"10.3389/fncel.2024.1471005","DOIUrl":"10.3389/fncel.2024.1471005","url":null,"abstract":"<p><strong>Introduction: </strong>Activation of NLRP3-containing inflammasome, which is responsible for IL-1β maturation, has been shown to contribute to Alzheimer's disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown.</p><p><strong>Methods: </strong>NLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and <i>Nlrp3</i> knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of <i>Nlrp3</i> knockout and wild-type mice were cultured, treated with IL-1β and H<sub>2</sub>O<sub>2</sub> at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ antibody.</p><p><strong>Results: </strong>Deficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated <i>Osteopontin</i> gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H<sub>2</sub>O<sub>2</sub> increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner.</p><p><strong>Discussion: </strong>Inhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer's patients.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1471005"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617626","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}
Mg-Li alloys can be promising candidates as bioresorbable Li-releasing implants for bipolar disorder and other neurodegenerative disorders. In order to compare the therapeutic efficacy of conventional Li salts and Li delivered through Mg-Li alloy extracts, we tested an in vitro model based on the neuroinflammation hypothesis of mood disorders (peripheral inflammation inducing neuroinflammation) wherein, a coculture of microglia and astrocytes was treated with conditioned medium from pro-inflammatory macrophages. Two alloys, Mg-1.6Li and Mg-9.5Li, were tested in the form of material extracts and well-known outcomes of Li treatment such as GSK3β phosphorylation (indirect flow cytometry) and influence on inflammation-related gene expression (qPCR) were compared against Li salts. This is the first study demonstrating that Li can increase the phosphorylation of GSK3β in glial cells in the presence of excess Mg. Furthermore, Mg-Li alloys were more effective than Li salts in downregulating IL6 and upregulating the neurotrophin GDNF. Mg had no antagonistic effects toward Li-driven downregulation of astrogliosis markers. Overall, the results provide evidence to support further studies employing Mg-Li alloys for neurological applications.
{"title":"Application of an <i>in vitro</i> neuroinflammation model to evaluate the efficacy of magnesium-lithium alloys.","authors":"Krathika Bhat, Heike Helmholz, Regine Willumeit-Römer","doi":"10.3389/fncel.2024.1485427","DOIUrl":"10.3389/fncel.2024.1485427","url":null,"abstract":"<p><p>Mg-Li alloys can be promising candidates as bioresorbable Li-releasing implants for bipolar disorder and other neurodegenerative disorders. In order to compare the therapeutic efficacy of conventional Li salts and Li delivered through Mg-Li alloy extracts, we tested an <i>in vitro</i> model based on the neuroinflammation hypothesis of mood disorders (peripheral inflammation inducing neuroinflammation) wherein, a coculture of microglia and astrocytes was treated with conditioned medium from pro-inflammatory macrophages. Two alloys, Mg-1.6Li and Mg-9.5Li, were tested in the form of material extracts and well-known outcomes of Li treatment such as GSK3β phosphorylation (indirect flow cytometry) and influence on inflammation-related gene expression (qPCR) were compared against Li salts. This is the first study demonstrating that Li can increase the phosphorylation of GSK3β in glial cells in the presence of excess Mg. Furthermore, Mg-Li alloys were more effective than Li salts in downregulating <i>IL6</i> and upregulating the neurotrophin <i>GDNF</i>. Mg had no antagonistic effects toward Li-driven downregulation of astrogliosis markers. Overall, the results provide evidence to support further studies employing Mg-Li alloys for neurological applications.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1485427"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617602","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}
Pub Date : 2024-10-29eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1493644
Frida Bällgren, Yang Hu, Shannuo Li, Lara van de Beek, Margareta Hammarlund-Udenaes, Irena Loryan
The pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter system facilitates the active net uptake of several marketed organic cationic drugs across the blood-brain barrier (BBB). This rare phenomenon has garnered interest in the H+/OC antiporter system as a potential target for CNS drug delivery. However, analysis of pharmacovigilance data has uncovered a significant association between substrates of the H+/OC antiporter and neurotoxicity, particularly drug-induced seizures (DIS) and mood- and cognitive-related adverse events (MCAEs). This preclinical study aimed to elucidate the CNS regional disposition of H+/OC antiporter substrates at therapeutically relevant plasma concentrations to uncover potential pharmacokinetic mechanisms underlying DIS and MCAEs. Here, we investigated the neuropharmacokinetics of pyrilamine, diphenhydramine, bupropion, tramadol, oxycodone, and memantine. Using the Combinatory Mapping Approach for Regions of Interest (CMA-ROI), we characterized the transport of unbound drugs across the BBB in specific CNS regions, as well as the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). Our findings demonstrated active net uptake across the BBB and BSCB, with unbound ROI-to-plasma concentration ratio, Kp,uu,ROI, values consistently exceeding unity in all assessed regions. Despite minor regional differences, no significant distinctions were found when comparing the whole brain to investigated regions of interest, indicating region-independent active transport. Furthermore, we observed intracellular accumulation via lysosomal trapping for all studied drugs. These results provide new insights into the CNS regional neuropharmacokinetics of these drugs, suggesting that while the brain uptake is region-independent, the active transport mechanism enables high extracellular and intracellular drug concentrations, potentially contributing to neurotoxicity. This finding emphasizes the necessity of thorough neuropharmacokinetic evaluation and neurotoxicity profiling in the development of drugs that utilize this transport pathway.
{"title":"Region-independent active CNS net uptake of marketed H<sup>+</sup>/OC antiporter system substrates.","authors":"Frida Bällgren, Yang Hu, Shannuo Li, Lara van de Beek, Margareta Hammarlund-Udenaes, Irena Loryan","doi":"10.3389/fncel.2024.1493644","DOIUrl":"https://doi.org/10.3389/fncel.2024.1493644","url":null,"abstract":"<p><p>The pyrilamine-sensitive proton-coupled organic cation (H<sup>+</sup>/OC) antiporter system facilitates the active net uptake of several marketed organic cationic drugs across the blood-brain barrier (BBB). This rare phenomenon has garnered interest in the H<sup>+</sup>/OC antiporter system as a potential target for CNS drug delivery. However, analysis of pharmacovigilance data has uncovered a significant association between substrates of the H<sup>+</sup>/OC antiporter and neurotoxicity, particularly drug-induced seizures (DIS) and mood- and cognitive-related adverse events (MCAEs). This preclinical study aimed to elucidate the CNS regional disposition of H<sup>+</sup>/OC antiporter substrates at therapeutically relevant plasma concentrations to uncover potential pharmacokinetic mechanisms underlying DIS and MCAEs. Here, we investigated the neuropharmacokinetics of pyrilamine, diphenhydramine, bupropion, tramadol, oxycodone, and memantine. Using the Combinatory Mapping Approach for Regions of Interest (CMA-ROI), we characterized the transport of unbound drugs across the BBB in specific CNS regions, as well as the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). Our findings demonstrated active net uptake across the BBB and BSCB, with unbound ROI-to-plasma concentration ratio, K<sub>p,uu,ROI</sub>, values consistently exceeding unity in all assessed regions. Despite minor regional differences, no significant distinctions were found when comparing the whole brain to investigated regions of interest, indicating region-independent active transport. Furthermore, we observed intracellular accumulation via lysosomal trapping for all studied drugs. These results provide new insights into the CNS regional neuropharmacokinetics of these drugs, suggesting that while the brain uptake is region-independent, the active transport mechanism enables high extracellular and intracellular drug concentrations, potentially contributing to neurotoxicity. This finding emphasizes the necessity of thorough neuropharmacokinetic evaluation and neurotoxicity profiling in the development of drugs that utilize this transport pathway.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1493644"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617828","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}
Pub Date : 2024-10-29eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1490607
Qi Wang, Lei Yuan, Fei Wang, Fei Sun
Background: Following ischemic stroke, non-neuronal cells within the nervous system play a crucial role in maintaining neurovascular unit functions, regulating metabolic and inflammatory processes of the nervous system. Investigating the functions and regulation of these cells, particularly immune cells, deepens our understanding of the complex mechanisms of neuroinflammation and immune modulation after ischemic stroke and provides new perspectives and methods for immune-related therapy.
Methods: The annual distribution, journals, authors, countries, institutions, and keywords of articles published between 2015 and 2024 were visualized and analyzed using CiteSpace and other bibliometric tools.
Results: A total of 1,089 relevant articles or reviews were included, demonstrating an overall upward trend; The terms "cerebral ischemia," "immune response," "brain ischemia," "cerebral inflammation," "neurovascular unit," and "immune infiltration," etc. are hot keywords in this field.
Conclusion: In recent years, research on immune-related therapy for ischemic stroke has focused on mechanisms of occurrence, protection and repair of the blood-brain barrier (BBB) by non-neuronal cells, and regulation of immunosuppression and inflammation. Among these, reducing BBB disruption to minimize secondary brain damage has become a hotspot. At the same time, the complex roles of immune responses have attracted attention, particularly the balance between regulatory T cells and Th17 cells in regulating neuroinflammation and promoting neurological function recovery, which is crucial to reduce secondary neuronal damage and improve prognosis, potentially establishing a pivotal frontier in this domain of investigation.
背景:缺血性脑卒中后,神经系统内的非神经元细胞在维持神经血管单元功能、调节神经系统代谢和炎症过程中发挥着至关重要的作用。研究这些细胞,尤其是免疫细胞的功能和调控,可以加深我们对缺血性脑卒中后神经炎症和免疫调节复杂机制的理解,并为免疫相关治疗提供新的视角和方法:使用CiteSpace和其他文献计量工具对2015年至2024年间发表的文章的年度分布、期刊、作者、国家、机构和关键词进行了可视化分析:共收录相关文章或综述1089篇,总体呈上升趋势;"脑缺血"、"免疫反应"、"脑缺血"、"脑部炎症"、"神经血管单元"、"免疫浸润 "等词是该领域的热门关键词:近年来,缺血性脑卒中的免疫相关治疗研究主要集中在非神经元细胞对血脑屏障(BBB)的发生、保护和修复机制,以及免疫抑制和炎症的调控等方面。其中,减少血脑屏障破坏以减少继发性脑损伤已成为研究热点。与此同时,免疫反应的复杂作用也备受关注,尤其是调节性 T 细胞和 Th17 细胞在调节神经炎症和促进神经功能恢复方面的平衡,这对于减少继发性神经元损伤和改善预后至关重要,有可能成为这一研究领域的关键前沿。
{"title":"Global research trends and prospects on immune-related therapy in ischemic stroke: a bibliometric analysis.","authors":"Qi Wang, Lei Yuan, Fei Wang, Fei Sun","doi":"10.3389/fncel.2024.1490607","DOIUrl":"https://doi.org/10.3389/fncel.2024.1490607","url":null,"abstract":"<p><strong>Background: </strong>Following ischemic stroke, non-neuronal cells within the nervous system play a crucial role in maintaining neurovascular unit functions, regulating metabolic and inflammatory processes of the nervous system. Investigating the functions and regulation of these cells, particularly immune cells, deepens our understanding of the complex mechanisms of neuroinflammation and immune modulation after ischemic stroke and provides new perspectives and methods for immune-related therapy.</p><p><strong>Methods: </strong>The annual distribution, journals, authors, countries, institutions, and keywords of articles published between 2015 and 2024 were visualized and analyzed using CiteSpace and other bibliometric tools.</p><p><strong>Results: </strong>A total of 1,089 relevant articles or reviews were included, demonstrating an overall upward trend; The terms \"cerebral ischemia,\" \"immune response,\" \"brain ischemia,\" \"cerebral inflammation,\" \"neurovascular unit,\" and \"immune infiltration,\" etc. are hot keywords in this field.</p><p><strong>Conclusion: </strong>In recent years, research on immune-related therapy for ischemic stroke has focused on mechanisms of occurrence, protection and repair of the blood-brain barrier (BBB) by non-neuronal cells, and regulation of immunosuppression and inflammation. Among these, reducing BBB disruption to minimize secondary brain damage has become a hotspot. At the same time, the complex roles of immune responses have attracted attention, particularly the balance between regulatory T cells and Th17 cells in regulating neuroinflammation and promoting neurological function recovery, which is crucial to reduce secondary neuronal damage and improve prognosis, potentially establishing a pivotal frontier in this domain of investigation.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1490607"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617700","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}
Pub Date : 2024-10-29eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1511314
Duraisamy Kempuraj, Stefania Ceruti
{"title":"Editorial: 15 years of frontiers in cellular neuroscience: blood brain barrier modulation and dysfunction in brain diseases.","authors":"Duraisamy Kempuraj, Stefania Ceruti","doi":"10.3389/fncel.2024.1511314","DOIUrl":"https://doi.org/10.3389/fncel.2024.1511314","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1511314"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617627","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}
Pub Date : 2024-10-28eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1483368
Vasileios Eftychidis, Tommas J Ellender, Jacek Szymanski, Liliana Minichiello
The hypothalamus is the primary center of the brain that regulates energy homeostasis. The ventromedial hypothalamus (VMH) plays a central role in maintaining energy balance by regulating food intake, energy expenditure, and glucose levels. However, the cellular and molecular mechanisms underlying its functions are still poorly understood. Cholecystokinin (CCK) is one of many genes expressed in this hypothalamic nucleus. Peripheral CCK regulates food intake, body weight, and glucose homeostasis. However, current research does not explain the function of CCK neurons in specific nuclei of the hypothalamus and their likely roles in network dynamics related to energy balance and food intake. This study uses genetic and pharmacological methods to examine the role of CCK-expressing neurons in the VMH (CCKVMH). Namely, using a previously generated BAC transgenic line expressing Cre recombinase under the CCK promoter, we performed targeted manipulations of CCKVMH neurons. Histological and transcriptomic database analysis revealed extensive distribution of these neurons in the VMH, with significant heterogeneity in gene expression related to energy balance, including co-expression with PACAP and somatostatin. Pharmacogenetic acute inhibition via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) resulted in increased food intake and altered meal patterns, characterized by higher meal frequency and shorter intermeal intervals. Furthermore, diphtheria toxin-mediated ablation of CCKVMH neurons led to significant weight gain and hyperphagia over time, increasing meal size and duration. These mice also exhibited impaired glucose tolerance, indicative of disrupted glucose homeostasis. Our findings underscore the integral role of CCKVMH neurons in modulating feeding behavior, energy homeostasis, and glucose regulation. This study enhances our understanding of the neurohormonal mechanisms underlying obesity and metabolic disorders, providing potential targets for therapeutic interventions.
{"title":"Cholecystokinin-expressing neurons of the ventromedial hypothalamic nucleus control energy homeostasis.","authors":"Vasileios Eftychidis, Tommas J Ellender, Jacek Szymanski, Liliana Minichiello","doi":"10.3389/fncel.2024.1483368","DOIUrl":"https://doi.org/10.3389/fncel.2024.1483368","url":null,"abstract":"<p><p>The hypothalamus is the primary center of the brain that regulates energy homeostasis. The ventromedial hypothalamus (VMH) plays a central role in maintaining energy balance by regulating food intake, energy expenditure, and glucose levels. However, the cellular and molecular mechanisms underlying its functions are still poorly understood. Cholecystokinin (CCK) is one of many genes expressed in this hypothalamic nucleus. Peripheral CCK regulates food intake, body weight, and glucose homeostasis. However, current research does not explain the function of CCK neurons in specific nuclei of the hypothalamus and their likely roles in network dynamics related to energy balance and food intake. This study uses genetic and pharmacological methods to examine the role of CCK-expressing neurons in the VMH (CCK<sup>VMH</sup>). Namely, using a previously generated BAC transgenic line expressing Cre recombinase under the CCK promoter, we performed targeted manipulations of CCK<sup>VMH</sup> neurons. Histological and transcriptomic database analysis revealed extensive distribution of these neurons in the VMH, with significant heterogeneity in gene expression related to energy balance, including co-expression with PACAP and somatostatin. Pharmacogenetic acute inhibition via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) resulted in increased food intake and altered meal patterns, characterized by higher meal frequency and shorter intermeal intervals. Furthermore, diphtheria toxin-mediated ablation of CCK<sup>VMH</sup> neurons led to significant weight gain and hyperphagia over time, increasing meal size and duration. These mice also exhibited impaired glucose tolerance, indicative of disrupted glucose homeostasis. Our findings underscore the integral role of CCK<sup>VMH</sup> neurons in modulating feeding behavior, energy homeostasis, and glucose regulation. This study enhances our understanding of the neurohormonal mechanisms underlying obesity and metabolic disorders, providing potential targets for therapeutic interventions.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1483368"},"PeriodicalIF":4.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617604","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}
Pub Date : 2024-10-25eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1505939
Jennifer Ihuoma, Sharon Negri, Amanda Morato Do Canto, Anika M S Hartz, Aditi Deshpande, Stefano Tarantini
{"title":"Editorial: Novel approaches to targeting the vasculature and metabolome to prevent brain aging and related diseases.","authors":"Jennifer Ihuoma, Sharon Negri, Amanda Morato Do Canto, Anika M S Hartz, Aditi Deshpande, Stefano Tarantini","doi":"10.3389/fncel.2024.1505939","DOIUrl":"https://doi.org/10.3389/fncel.2024.1505939","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1505939"},"PeriodicalIF":4.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11544536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617630","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}
Pub Date : 2024-10-25eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1491952
Duraisamy Kempuraj, Kirk D Dourvetakis, Jessica Cohen, Daniel Seth Valladares, Rhitik Samir Joshi, Sai Puneeth Kothuru, Tristin Anderson, Baskaran Chinnappan, Amanpreet K Cheema, Nancy G Klimas, Theoharis C Theoharides
Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.
神经血管单元(NVU)炎症通过激活神经胶质细胞和神经元损伤在神经退行性疾病中起着至关重要的作用。虽然疾病发病的确切机制尚不清楚,但某些生物标志物能为了解疾病的发病机制、严重程度、进展和疗效提供有价值的信息。这些标志物可用于评估脑细胞的病理生理状态,包括神经元、星形胶质细胞、小胶质细胞、少突胶质细胞、特化微血管内皮细胞、周细胞、NVU 和血脑屏障(BBB)破坏。血脑屏障的紧密连接(TJ)、粘连连接(AdJ)和间隙连接(GJ)成分受损或失调会导致包括神经退行性疾病在内的各种脑部疾病的通透性增加和神经炎症。因此,可以通过评估血液、脑脊液(CSF)或脑组织中的神经炎症标记物来确定神经系统疾病的严重程度、进展和治疗反应性。慢性炎症常见于与年龄相关的神经退行性疾病,包括阿尔茨海默病(AD)、帕金森病(PD)和痴呆症。神经创伤/创伤性脑损伤(TBI)也会导致急性和慢性神经炎症反应。某些标志物的表达也可能在神经退行性疾病发病前数年甚至数十年发生改变。在这篇综述中,我们将讨论与急性和慢性脑部疾病,尤其是与神经血管病变相关的神经炎症和神经退行性变的标志物。这些生物标志物可在脑脊液或脑组织中进行评估。神经丝蛋白(NfL)、泛素 C 端水解酶-L1(UCHL1)、胶质纤维酸性蛋白(GFAP)、电离钙结合适配分子 1(Iba-1)、跨膜蛋白 119(TMEM119)、水光素、内皮素-1 和血小板衍生生长因子受体 beta(PDGFRβ)是一些重要的神经炎症标志物。最近的芯片上的 BBB 模型为深入了解脑部疾病和神经治疗提供了广阔的前景。在临床实践中整合这些标记物有可能提高早期诊断、监测疾病进展和改善治疗效果。
{"title":"Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders.","authors":"Duraisamy Kempuraj, Kirk D Dourvetakis, Jessica Cohen, Daniel Seth Valladares, Rhitik Samir Joshi, Sai Puneeth Kothuru, Tristin Anderson, Baskaran Chinnappan, Amanpreet K Cheema, Nancy G Klimas, Theoharis C Theoharides","doi":"10.3389/fncel.2024.1491952","DOIUrl":"https://doi.org/10.3389/fncel.2024.1491952","url":null,"abstract":"<p><p>Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1491952"},"PeriodicalIF":4.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11544127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617642","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}
Pub Date : 2024-10-23eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1432002
Siva Sundara Kumar Durairajan, Karthikeyan Selvarasu, Abhay Kumar Singh, Supriti Patnaik, Ashok Iyaswamy, Yogini Jaiswal, Leonard L Williams, Jian-Dong Huang
Alzheimer's disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin's responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1's anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.
阿尔茨海默病(AD)的特征是中枢神经系统的神经细胞随着年龄的增长而逐渐退化。在受阿尔茨海默病影响的大脑中观察到的组织病理学特征是细胞外和细胞内淀粉样蛋白-β的异常堆积,以及由过度磷酸化的tau蛋白组成的神经纤维缠结的形成。轴突运输是货物沿轴突移动的基本过程,依赖于驱动蛋白和动力蛋白等分子马达。驱动蛋白负责在神经元内运输重要的货物,因此它的功能障碍与在 AD 中观察到的轴突运输受损有关。轴突运输受损、分子马达蛋白功能障碍以及信号通路失调是导致突触受损和认知能力下降的重要原因。微管相关蛋白 tau 的失调是一个核心因素,它破坏了微管的稳定性并干扰了驱动蛋白-1 的运输。驱动蛋白-1 超家族成员,包括驱动蛋白家族成员 5A、5B 和 5C,以及驱动蛋白轻链,与 AD 病理学有着错综复杂的联系。然而,驱动蛋白家族成员在 AD 患者中的含量并不一致,因此有必要进一步探讨这些运动蛋白对神经退行性病变和轴突运输障碍的机理影响。这篇综述强调了驱动蛋白-1 在 AD 中逆行运输的重要性。它强调了研究运动蛋白对各种神经系统疾病影响的潜在机制的必要性。尽管目前的科学文献还存在局限性,但我们的研究主张以驱动蛋白和自噬功能障碍为靶点,将其作为对 AD 进行新型治疗干预和诊断的可行途径。
{"title":"Unraveling the interplay of kinesin-1, tau, and microtubules in neurodegeneration associated with Alzheimer's disease.","authors":"Siva Sundara Kumar Durairajan, Karthikeyan Selvarasu, Abhay Kumar Singh, Supriti Patnaik, Ashok Iyaswamy, Yogini Jaiswal, Leonard L Williams, Jian-Dong Huang","doi":"10.3389/fncel.2024.1432002","DOIUrl":"10.3389/fncel.2024.1432002","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin's responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1's anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1432002"},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590377","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}