Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired eli...Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.展开更多
The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disord...The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic diseases.Systemic diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous system.This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation.In addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and neurodegeneration.Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.展开更多
Cognitive dysfunction is one of the common central nervous systems(CNS)complications of diabetes mellitus,which seriously affects the quality of life of patients and results in a huge economic burden.The glymphatic sy...Cognitive dysfunction is one of the common central nervous systems(CNS)complications of diabetes mellitus,which seriously affects the quality of life of patients and results in a huge economic burden.The glymphatic system dysfunction mediated by aquaporin-4(AQP4)loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment(DCI).However,the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear.Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators.Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus,and skeletal muscle,liver and adipose tissue are the key target insulin resistance organs.In this review,the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed.We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet,which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI.Furthermore,the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized,which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.展开更多
The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vesse...The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.展开更多
Recent studies have proposed three lymphatic drainage systems in the brain,that is,the glymphatic system,the intramural periarterial drainage pathway,and meningeal lymphatic vessels,whose roles in various neurological...Recent studies have proposed three lymphatic drainage systems in the brain,that is,the glymphatic system,the intramural periarterial drainage pathway,and meningeal lymphatic vessels,whose roles in various neurological diseases have been widely explored.The glymphatic system is a fluid drainage and waste clearance pathway that utilizes perivascular space and aquaporin-4 protein located in the astrocyte endfeet to provide a space for exchange of cerebrospinal fluid and interstitial fluid.The intramural periarterial drainage pathway drives the flow of interstitial fluid through the capillary basement membrane and the arterial tunica media.Meningeal lymphatic vessels within the dura mater are involved in the removal of cerebral macromolecules and immune responses.After ischemic stroke,impairment of these systems could lead to cerebral edema,accumulation of toxic factors,and activation of neuroinflammation,while restoration of their normal functions can improve neurological outcomes.In this review,we summarize the basic concepts of these drainage systems,including drainage routes,physiological functions,regulatory mechanisms,and detection technologies.We also focus on the roles of lymphatic drainage systems in brain injury after ischemic stroke,as well as recent advances in therapeutic strategies targeting these drainage systems.These findings provide information for potential novel strategies for treatment of stroke.展开更多
Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential compone...Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential components in neurovascular units,glial cells and blood vessels(including the bloodbrain barrier)together maintain an optimal microenvironment for neuronal function.They provide nutrients,regulate neuronal excitability,and prevent harmful substances from entering brain tissue.The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis,supporting neuronal function,and reacting to injuries.However,most studies have focused on postmortem animals,which inevitably lack critical information about the dynamic changes that occur after ischemic stroke.Therefore,a high-precision technique for research in living animals is urgently needed.Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions.Twophoton fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure,information on multicellular component interactions,and provide images of structure and function in the cranial window.This technique shifts the existing research paradigm from static to dynamic,from flat to stereoscopic,and from single-cell function to multicellular intercommunication,thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain.In this review,we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy,highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems.We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.展开更多
Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of t...Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system;however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined;however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.展开更多
Water is the key medium to transport numerous constituents and to provide a platform for physiological processes to take place in the living organisms in general;it also participates actively in many of these processe...Water is the key medium to transport numerous constituents and to provide a platform for physiological processes to take place in the living organisms in general;it also participates actively in many of these processes. In humans, there are different vehicles to contain water and its constituents. Our objective is to find out whether there is an overall water-base circulation system in the human body by analyzing the updated findings of different research groups on the physiological functions of various seemingly isolated fluid systems. By 1963, there were five separate fluid systems discovered in mammalians: (i) The Primo Vasculature Fluid (PVF) with protein precursors and micro cells held in the Primo Vasculature System (PVS). (ii) Blood with its constituents held in the cardio vasculature. (iii) Extracranial interstitial fluid (ISF) whose vehicle had a very irregular structure—the interstitium all over the body. (iv) The cerebrospinal fluid had been considered to be within the brain ventricles and spinal canal. (v) The extra-cranial lymphatic system which drained ISF, and had been known to join the subclavian vein. Fluid (i) was first reported in 1963 and fluids (ii) to (v) have been known for many decades, but the failure to detect a lymphatic system inside the skull has also been a mystery for many decades. The intra-cranial ISF (which we name as BISF) has drawn little attention, apart from discussing the mechanism of the blood-brain-barrier. During the past decade, there has been direct evidence indicating that CSF and BISF are actually mixed. After that, the intracranial lymphatic system was discovered and confirmed in animal models only slightly over one year back, and we called such fluid as glymphatic-fluid. After reviewing the stated “classical” five fluid systems together with the new findings in Sections 2 - 7, we propose, for the first time, that the PVF, the blood, ISF, a mixture of CSF-BISF, and a mixture of glymphatic-fluid and lymph form an integrative circulation system in water base in the human and other mammalian bodies, as schematically represented in the last section. In this paper, we point out the positive correlation of chronic neuro degenerative diseases such as Alzheimer’s disease, Parkinson’s diseases and the insufficient brain wastes clearance by the glymphatic system. We also discuss the role played by the venous vessels as part of such clearance in upright posture. Moreover, simple non-invasive maneuver techniques are introduced here, as one example of enhancement of glymphatic fluid flow out of the skull to join the lymphatic system. A series of questions are raised in Section 8, the answers to which would help us to understand the transition from physio- to pathological states in the development of many diseases. Detailed analysis of this paper leads us to consider that research in understanding this integrative circulation system is only at the infancy stage, and fluid dynamics investigation seems to be the plausible modality of approach in the near future.展开更多
Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Re...Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Recently,it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases.The ability to clear metabolic waste is essential for tissue homeostasis in mammals,including humans.While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions,there is growing evidence of a glymphatic system in the central nervous system,which structurally includes the optic nerve.Named to acknowledge the supportive role of astroglial cells,this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system.Herein,we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve.We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents,aquaporin 4-null rodents,and humans;glymphatic imaging studies in diseases where the optic nerve is impaired;and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health.We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.展开更多
The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully unders...The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.展开更多
目的通过文献计量学的方法分析2013—2023年血管周围间隙的研究现状、热点及前沿领域。方法在Web of Science核心合集数据库中检索2013年1月1日—2023年6月19日血管周围间隙相关英文论著。使用CiteSpace V6.3.R1软件分析文献的发文国家...目的通过文献计量学的方法分析2013—2023年血管周围间隙的研究现状、热点及前沿领域。方法在Web of Science核心合集数据库中检索2013年1月1日—2023年6月19日血管周围间隙相关英文论著。使用CiteSpace V6.3.R1软件分析文献的发文国家、研究机构、作者的合作网络,参考文献、第一作者、期刊的共被引网络,关键词的共现网络,关键词及参考文献共被引的突现情况;使用VOSviewer 1.6.15软件对关键词进行聚类分析。结果共纳入1549篇文献。2013—2023年的年发文量整体呈增长趋势。美国的发文量最多,其次为中国。发文量位列前3的研究机构分别是哈佛大学、麻省总医院和爱丁堡大学。合作网络分析发现国家间合作相对紧密,国内研究机构与其他研究机构合作较少。爱丁堡大学的Wardlaw Joanna M发文量最多。关键词共现图谱显示前10个高频关键词分别为小血管病、扩大的血管周围间隙、MRI、脑、Virchow-Robin间隙、阿尔茨海默病、痴呆、风险、卒中和类淋巴系统。关键词聚类分析发现脑小血管病、痴呆、MRI为当前研究热点,类淋巴系统为新兴的研究方向。关键词突现分析表明弥散成像从2021年至今备受关注。结论近10年血管周围间隙的研究热度逐年攀升。脑小血管病是主要的研究热点,类淋巴系统为新兴的研究方向,前沿领域为弥散张量成像等MRI技术。展开更多
Type of the lymphatic system is a new concept put forward by foreign scholars in recent years.It is similar to the lymphatic system,is the brain of the internal fluid metabolism channel and its metabolites in the brai...Type of the lymphatic system is a new concept put forward by foreign scholars in recent years.It is similar to the lymphatic system,is the brain of the internal fluid metabolism channel and its metabolites in the brain plays a major role in the process of removal,sleep disorders in alzheimer's disease brain stroke,traumatic brain injury and other central nervous system diseases.The Tri-jiao theory is a very important in traditional Chinese medicine plate structure,it is from the function to traffic from running water channel,but still no definite conclusion on structure.This paper attempts to explore the relationship between trioke and the lymphatic system and their influence on Alzheimer's disease through modern medical research on the lymphatic system,so as to provide new inspirations for the treatment of Alzheimer's disease.展开更多
In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that hav...In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.展开更多
The experimental research, presented in the study, focuses on track tests with the aim of highlighting changes in lap times after manipulative treatment of drainage of the glymphatic system and stimulation of the symp...The experimental research, presented in the study, focuses on track tests with the aim of highlighting changes in lap times after manipulative treatment of drainage of the glymphatic system and stimulation of the sympathetic nervous system. Introduction: The experimental research, presented in this study, focuses on analyzing the potential effects of a manipulative treatment on the performance of a professional driver. The main objective is to evaluate the change in lap times after the application of the treatment, trying to understand whether it can actually positively influence the driver’s performance. The study stands an important opportunity to extend knowledge, regarding the use of manipulative therapies in the context of optimized driving skills. The results obtained could provide useful insights and contribute to improving the performance of professional drivers by offering new perspectives and strategies to improve their performance. Leveraging a rigorous scientific approach and a sample of highly skilled drivers, the research aims to provide concrete evidence on the effectiveness of manipulative treatment in driving skills. Monitoring lap times before and after the intervention also capture any temporary or long-term effects of the treatment, ensuring a thorough and reliable analysis of the results. Materials and methods: 15 professional drivers, aged 18 to 36 years, with at least 10 years of experience as drivers, participated in this study. The test consisted of analyzing lap times before and after treatment.展开更多
基金supported by the National Key R&D Program of China,No.2021YFF0702203(to HYL)the National Natural Science Foundation of China,No.82101323(to TS)Preferred Foundation of Zhejiang Postdoctors,No.ZJ2021152(to TS).
文摘Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.
基金supported by the National Natural Science Foundation of China,Nos.82071249 and 81771207 (both to CH)。
文摘The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic diseases.Systemic diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous system.This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation.In addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and neurodegeneration.Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.
基金supported by the National Natural Science Foundation of China(No.82174112)。
文摘Cognitive dysfunction is one of the common central nervous systems(CNS)complications of diabetes mellitus,which seriously affects the quality of life of patients and results in a huge economic burden.The glymphatic system dysfunction mediated by aquaporin-4(AQP4)loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment(DCI).However,the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear.Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators.Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus,and skeletal muscle,liver and adipose tissue are the key target insulin resistance organs.In this review,the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed.We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet,which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI.Furthermore,the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized,which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.
基金supported by the Key Program of the National Natural Science Foundation of ChinaNo.82030071+1 种基金the Science and Technology Major Project of ChangshaNo.kh2103008 (both to JZH)
文摘The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.
基金supported by the Natural Science Foundation of Beijing(Key Program)No.Z200025(to JHY)+1 种基金the National Natural Science Foundation of China,No.81873818(to LHQ)Supporting Platform Construction Project of Peking University Health Science Center,No.BMU2021ZC011(to JHY).
文摘Recent studies have proposed three lymphatic drainage systems in the brain,that is,the glymphatic system,the intramural periarterial drainage pathway,and meningeal lymphatic vessels,whose roles in various neurological diseases have been widely explored.The glymphatic system is a fluid drainage and waste clearance pathway that utilizes perivascular space and aquaporin-4 protein located in the astrocyte endfeet to provide a space for exchange of cerebrospinal fluid and interstitial fluid.The intramural periarterial drainage pathway drives the flow of interstitial fluid through the capillary basement membrane and the arterial tunica media.Meningeal lymphatic vessels within the dura mater are involved in the removal of cerebral macromolecules and immune responses.After ischemic stroke,impairment of these systems could lead to cerebral edema,accumulation of toxic factors,and activation of neuroinflammation,while restoration of their normal functions can improve neurological outcomes.In this review,we summarize the basic concepts of these drainage systems,including drainage routes,physiological functions,regulatory mechanisms,and detection technologies.We also focus on the roles of lymphatic drainage systems in brain injury after ischemic stroke,as well as recent advances in therapeutic strategies targeting these drainage systems.These findings provide information for potential novel strategies for treatment of stroke.
基金supported by grants from the National Natural Science Foundation of China,Nos.92148206,82071330(to ZPT)82201745(to HN)the Natural Science Foundation of Hubei Province,China,Nos.2021BCA109(to ZPT)and 2021CFB067(to HN)。
文摘Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential components in neurovascular units,glial cells and blood vessels(including the bloodbrain barrier)together maintain an optimal microenvironment for neuronal function.They provide nutrients,regulate neuronal excitability,and prevent harmful substances from entering brain tissue.The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis,supporting neuronal function,and reacting to injuries.However,most studies have focused on postmortem animals,which inevitably lack critical information about the dynamic changes that occur after ischemic stroke.Therefore,a high-precision technique for research in living animals is urgently needed.Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions.Twophoton fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure,information on multicellular component interactions,and provide images of structure and function in the cranial window.This technique shifts the existing research paradigm from static to dynamic,from flat to stereoscopic,and from single-cell function to multicellular intercommunication,thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain.In this review,we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy,highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems.We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.
基金research fellowship awards made to IFH from Alzheimer’s Research UK(ARUK-RF2019A-003)and Parkinson’s UK(F-1902).
文摘Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system;however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined;however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.
文摘Water is the key medium to transport numerous constituents and to provide a platform for physiological processes to take place in the living organisms in general;it also participates actively in many of these processes. In humans, there are different vehicles to contain water and its constituents. Our objective is to find out whether there is an overall water-base circulation system in the human body by analyzing the updated findings of different research groups on the physiological functions of various seemingly isolated fluid systems. By 1963, there were five separate fluid systems discovered in mammalians: (i) The Primo Vasculature Fluid (PVF) with protein precursors and micro cells held in the Primo Vasculature System (PVS). (ii) Blood with its constituents held in the cardio vasculature. (iii) Extracranial interstitial fluid (ISF) whose vehicle had a very irregular structure—the interstitium all over the body. (iv) The cerebrospinal fluid had been considered to be within the brain ventricles and spinal canal. (v) The extra-cranial lymphatic system which drained ISF, and had been known to join the subclavian vein. Fluid (i) was first reported in 1963 and fluids (ii) to (v) have been known for many decades, but the failure to detect a lymphatic system inside the skull has also been a mystery for many decades. The intra-cranial ISF (which we name as BISF) has drawn little attention, apart from discussing the mechanism of the blood-brain-barrier. During the past decade, there has been direct evidence indicating that CSF and BISF are actually mixed. After that, the intracranial lymphatic system was discovered and confirmed in animal models only slightly over one year back, and we called such fluid as glymphatic-fluid. After reviewing the stated “classical” five fluid systems together with the new findings in Sections 2 - 7, we propose, for the first time, that the PVF, the blood, ISF, a mixture of CSF-BISF, and a mixture of glymphatic-fluid and lymph form an integrative circulation system in water base in the human and other mammalian bodies, as schematically represented in the last section. In this paper, we point out the positive correlation of chronic neuro degenerative diseases such as Alzheimer’s disease, Parkinson’s diseases and the insufficient brain wastes clearance by the glymphatic system. We also discuss the role played by the venous vessels as part of such clearance in upright posture. Moreover, simple non-invasive maneuver techniques are introduced here, as one example of enhancement of glymphatic fluid flow out of the skull to join the lymphatic system. A series of questions are raised in Section 8, the answers to which would help us to understand the transition from physio- to pathological states in the development of many diseases. Detailed analysis of this paper leads us to consider that research in understanding this integrative circulation system is only at the infancy stage, and fluid dynamics investigation seems to be the plausible modality of approach in the near future.
基金supported by National Institutes of Health,No.R01-EY028125Bright Focus Foundation,No.G2019103+2 种基金Feldstein Medical FoundationResearch to Prevent Blindness/Stavros Niarchos Foundation International Research Collaborators Awardan unrestricted grant from Research to Prevent Blindness to NYU Langone Health Department of Ophthalmology(to KCC)。
文摘Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Recently,it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases.The ability to clear metabolic waste is essential for tissue homeostasis in mammals,including humans.While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions,there is growing evidence of a glymphatic system in the central nervous system,which structurally includes the optic nerve.Named to acknowledge the supportive role of astroglial cells,this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system.Herein,we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve.We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents,aquaporin 4-null rodents,and humans;glymphatic imaging studies in diseases where the optic nerve is impaired;and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health.We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.
文摘The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.
文摘Type of the lymphatic system is a new concept put forward by foreign scholars in recent years.It is similar to the lymphatic system,is the brain of the internal fluid metabolism channel and its metabolites in the brain plays a major role in the process of removal,sleep disorders in alzheimer's disease brain stroke,traumatic brain injury and other central nervous system diseases.The Tri-jiao theory is a very important in traditional Chinese medicine plate structure,it is from the function to traffic from running water channel,but still no definite conclusion on structure.This paper attempts to explore the relationship between trioke and the lymphatic system and their influence on Alzheimer's disease through modern medical research on the lymphatic system,so as to provide new inspirations for the treatment of Alzheimer's disease.
基金supported by a grant from the Fundacao para a Ciencia e Tecnologia of the Ministerio da Educacao e Ciencia (2020.02006.CEECIND)iBiMED,University of Aveiro and the Fundacao para a Ciência e Tecnologia of the Ministerio da Educacao e Ciencia (to DT)。
文摘In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.
文摘The experimental research, presented in the study, focuses on track tests with the aim of highlighting changes in lap times after manipulative treatment of drainage of the glymphatic system and stimulation of the sympathetic nervous system. Introduction: The experimental research, presented in this study, focuses on analyzing the potential effects of a manipulative treatment on the performance of a professional driver. The main objective is to evaluate the change in lap times after the application of the treatment, trying to understand whether it can actually positively influence the driver’s performance. The study stands an important opportunity to extend knowledge, regarding the use of manipulative therapies in the context of optimized driving skills. The results obtained could provide useful insights and contribute to improving the performance of professional drivers by offering new perspectives and strategies to improve their performance. Leveraging a rigorous scientific approach and a sample of highly skilled drivers, the research aims to provide concrete evidence on the effectiveness of manipulative treatment in driving skills. Monitoring lap times before and after the intervention also capture any temporary or long-term effects of the treatment, ensuring a thorough and reliable analysis of the results. Materials and methods: 15 professional drivers, aged 18 to 36 years, with at least 10 years of experience as drivers, participated in this study. The test consisted of analyzing lap times before and after treatment.
