scholarly journals The glymphatic system and its role in cerebral homeostasis

2020 ◽  
Vol 129 (6) ◽  
pp. 1330-1340
Author(s):  
Helene Benveniste ◽  
Rena Elkin ◽  
Paul M. Heerdt ◽  
Sunil Koundal ◽  
Yuechuan Xue ◽  
...  
Keyword(s):  
Brain Parenchyma ◽  
Toxic Waste ◽  
Normal Brain ◽  
Fluid Exchange ◽  
Glymphatic System ◽  
The Past ◽  
System A ◽  
Waste Production ◽  
Lymphatic Vasculature ◽  
The Brain

The brain’s high bioenergetic state is paralleled by high metabolic waste production. Authentic lymphatic vasculature is lacking in brain parenchyma. Cerebrospinal fluid (CSF) flow has long been thought to facilitate central nervous system detoxification in place of lymphatics, but the exact processes involved in toxic waste clearance from the brain remain incompletely understood. Over the past 8 yr, novel data in animals and humans have begun to shed new light on these processes in the form of the “glymphatic system,” a brain-wide perivascular transit passageway dedicated to CSF transport and interstitial fluid exchange that facilitates metabolic waste drainage from the brain. Here we will discuss glymphatic system anatomy and methods to visualize and quantify glymphatic system (GS) transport in the brain and also discuss physiological drivers of its function in normal brain and in neurodegeneration.

scholarly journals Glymphatic System in the Central Nervous System, a Novel Therapeutic Direction Against Brain Edema After Stroke

2021 ◽  
Vol 13 ◽  
Author(s):  
Xiangyue Zhou ◽  
Youwei Li ◽  
Cameron Lenahan ◽  
Yibo Ou ◽  
Minghuan Wang ◽  
...  
Keyword(s):  
Brain Edema ◽  
Brain Tissue ◽  
Molecular Mechanisms ◽  
Glymphatic System ◽  
System A ◽  
Function Recovery ◽  
The Central Nervous System ◽  
The Stability ◽  
The Brain

Stroke is the destruction of brain function and structure, and is caused by either cerebrovascular obstruction or rupture. It is a disease associated with high mortality and disability worldwide. Brain edema after stroke is an important factor affecting neurologic function recovery. The glymphatic system is a recently discovered cerebrospinal fluid (CSF) transport system. Through the perivascular space and aquaporin 4 (AQP4) on astrocytes, it promotes the exchange of CSF and interstitial fluid (ISF), clears brain metabolic waste, and maintains the stability of the internal environment within the brain. Excessive accumulation of fluid in the brain tissue causes cerebral edema, but the glymphatic system plays an important role in the process of both intake and removal of fluid within the brain. The changes in the glymphatic system after stroke may be an important contributor to brain edema. Understanding and targeting the molecular mechanisms and the role of the glymphatic system in the formation and regression of brain edema after stroke could promote the exclusion of fluids in the brain tissue and promote the recovery of neurological function in stroke patients. In this review, we will discuss the physiology of the glymphatic system, as well as the related mechanisms and therapeutic targets involved in the formation of brain edema after stroke, which could provide a new direction for research against brain edema after stroke.

scholarly journals Metabolic Plasticity of Astrocytes and Aging of the Brain

2019 ◽  
Vol 20 (4) ◽  
pp. 941 ◽  
Author(s):  
Mitsuhiro Morita ◽  
Hiroko Ikeshima-Kataoka ◽  
Marko Kreft ◽  
Nina Vardjan ◽  
Robert Zorec ◽  
...  
Keyword(s):  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Acid Oxidation ◽  
Normal Brain ◽  
Atp Production ◽  
Metabolic Plasticity ◽  
Neuronal Synapses ◽  
Age Related ◽  
Pathologic Processes ◽  
The Brain

As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions.

scholarly journals Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function

2019 ◽  
Vol 4 (2) ◽  
pp. 90-92 ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Quan Jiang ◽  
Zhenggang Zhang
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Impairment ◽  
Interstitial Fluid ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Glymphatic System ◽  
Impaired Cognitive Function ◽  
Increased Risk ◽  
The Brain

Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.

scholarly journals Physiology of Microglia

2011 ◽  
Vol 91 (2) ◽  
pp. 461-553 ◽  
Author(s):  
Helmut Kettenmann ◽  
Uwe-Karsten Hanisch ◽  
Mami Noda ◽  
Alexei Verkhratsky
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Brain Parenchyma ◽  
Microglial Cells ◽  
Activation Process ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Cellular Compartments ◽  
The Brain

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

scholarly journals Cerebrospinal Fluid and Interstitial Fluid Motion via the Glymphatic Pathway Modelled by Optimal Mass Transport

2016 ◽  
Author(s):  
Vadim Ratner ◽  
Yi Gao ◽  
Hedok Lee ◽  
Maikan Nedergaard ◽  
Helene Benveniste ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Interstitial Fluid ◽  
Initial Conditions ◽  
Fluid Motion ◽  
Flow Patterns ◽  
Brain Parenchyma ◽  
Fluid Exchange ◽  
Waste Products ◽  
Glymphatic Pathway ◽  
The Brain

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the `glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs [1,2]. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through peri-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach [3] to model the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data.

The glymphatic system and meningeal lymphatics of the brain: new understanding of brain clearance

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Galina Yankova ◽  
Olga Bogomyakova ◽  
Andrey Tulupov
Keyword(s):  
Neurodegenerative Diseases ◽  
Brain Injuries ◽  
Immune Surveillance ◽  
Lymphatic Vessels ◽  
Drainage System ◽  
Waste Products ◽  
Glymphatic System ◽  
System A ◽  
Age Related ◽  
The Brain

Abstract The glymphatic system and meningeal lymphatics have recently been characterized. Glymphatic system is a glia-dependent system of perivascular channels, and it plays an important role in the removal of interstitial metabolic waste products. The meningeal lymphatics may be a key drainage route for cerebrospinal fluid into the peripheral blood, may contribute to inflammatory reaction and central nervous system (CNS) immune surveillance. Breakdowns and dysfunction of the glymphatic system and meningeal lymphatics play a crucial role in age-related brain changes, the pathogenesis of neurovascular and neurodegenerative diseases, as well as in brain injuries and tumors. This review discusses the relationship recently characterized meningeal lymphatic vessels with the glymphatic system, which provides perfusion of the CNS with cerebrospinal and interstitial fluids. The review also presents the results of human studies concerning both the presence of meningeal lymphatics and the glymphatic system. A new understanding of how aging, medications, sleep and wake cycles, genetic predisposition, and even body posture affect the brain drainage system has not only changed the idea of brain fluid circulation but has also contributed to an understanding of the pathology and mechanisms of neurodegenerative diseases.

ABC Transporters in Neurological Disorders: An Important Gateway for Botanical Compounds Mediated Neuro-Therapeutics

2019 ◽  
Vol 19 (10) ◽  
pp. 795-811 ◽  
Author(s):  
Niraj Kumar Jha ◽  
Rohan Kar ◽  
Rituraj Niranjan
Keyword(s):  
Abc Transporters ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Normal Brain ◽  
Neurological Outcomes ◽  
Age Related ◽  
Number Of Factors ◽  
Vector Borne ◽  
The Brain

Neurodegeneration is a distinguishing feature of many age related disorders and other vector borne neuroinflammatory diseases. There are a number of factors that can modulate the pathology of these disorders. ATP-binding cassette (ABC) transporters are primarily involved in the maintenance of normal brain homeostasis by eliminating toxic peptides and compounds from the brain. Also, ABC transporters protect the brain from the unwanted effects of endogenous and exogenous toxins that can enter the brain parenchyma. Therefore, these transporters have the ability to determine the pathological outcomes of several neurological disorders. For instance, ABC transporters like P-glycoprotein (ABCB1), and BCRP (ABCG2) have been reported to facilitate the clearance of peptides such as amyloid-β (Aβ) that accumulate in the brain during Alzheimer’s disease (AD) progression. Other members such as ABCA1, ABCA2, ABCC8, ABCC9, ABCG1 and ABCG4 also have been reported to be involved in the progression of various brain disorders such as HIV-associated dementia, Multiple sclerosis (MS), Ischemic stroke, Japanese encephalitis (JE) and Epilepsy. However, these defective transporters can be targeted by numerous botanical compounds such as Verapamil, Berberine and Fascalpsyn as a therapeutic target to treat these neurological outcomes. These compounds are already reported to modulate ABC transporter activity in the CNS. Nonetheless, the exact mechanisms involving the ABC transporters role in normal brain functioning, their role in neuronal dysfunction and how these botanical compounds ensure and facilitate their therapeutic action in association with defective transporters still remain elusive. This review therefore, summarizes the role of ABC transporters in neurological disorders, with a special emphasis on its role in AD brains. The prospect of using botanical/natural compounds as modulators of ABC transporters in neurological disorders is discussed in the latter half of the article.

scholarly journals The Glymphatic System (En)during Inflammation

2021 ◽  
Vol 22 (14) ◽  
pp. 7491
Author(s):  
Frida Lind-Holm Mogensen ◽  
Christine Delle ◽  
Maiken Nedergaard
Keyword(s):  
Fluid Transport ◽  
Neurological Diseases ◽  
Lymphatic Vessels ◽  
Perivascular Spaces ◽  
Fluid Exchange ◽  
Glymphatic System ◽  
The Central Nervous System ◽  
The Brain ◽  
Privileged Site ◽  
Vascular Compartment

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

scholarly journals MRI-Based Demonstration of The Normal Glymphatic System in a Human Population: A Systematic Review

2021 ◽  
Author(s):  
Min Kyoung Lee ◽  
Se Jin Cho ◽  
Yun Jung Bae ◽  
Jong-Min Kim
Keyword(s):  
Systematic Review ◽  
Human Population ◽  
Contrast Material ◽  
Brain Parenchyma ◽  
Cervical Lymph Nodes ◽  
Imaging Protocol ◽  
Glymphatic System ◽  
Current Systematic Review ◽  
Human Participants ◽  
The Brain

Abstract The glymphatic system has been described as the exchange between cerebrospinal fluid and interstitial fluid. Recently, many studies have demonstrated the presence of the glymphatic system based on MRI. The purpose of our study is to systematically review the studies demonstrating normal glymphatic system in a human population using MRI, and to find a detailed imaging protocol for the glymphatic system. We searched the MEDLINE and EMBASE databases to identify studies with human participants that contained MRI-based demonstrations of the normal glymphatic system. We extracted data on the imaging sequence, imaging protocol, and the targeted anatomical structures on each study. According to studies using contrast-enhanced MRI, peak enhancement was sequentially detected first in the CSF space, followed by the brain parenchyma, the meningeal lymphatic vessel (MLV), and finally the cervical lymph nodes, which corresponds to the glymphatic flow. Non-contrast flow-sensitive MRI showed similar results of glymphatic inflow from the CSF space to the brain parenchyma and efflux from the brain parenchyma to the MLV. Based on current systematic review, we recommended T1-weighted MRI using contrast material to visualize the glymphatic system. Our result can increase understanding of the glymphatic system and may lay the groundwork for future development of a standard imaging protocol.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

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