Authors: Jeffrey J Iliff, Minghuan Wang, Yonghong Liao...

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

Topics: Amyloid beta-Peptides; Animals; Aquaporin 4; Astrocytes; Biological Transport; Brain; Cerebral Ventricles; Cerebrospinal Fluid; Extracellular Fluid; Imaging, Three-Dimensional; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence, Multiphoton; Water

PubMed: 22896675
DOI: 10.1126/scitranslmed.3003748

Authors: Aleksanteri Aspelund, Salli Antila, Steven T Proulx...

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.

Topics: Analysis of Variance; Animals; Brain; Cerebrospinal Fluid; Extracellular Fluid; Fluorescent Antibody Technique; Galactosides; Green Fluorescent Proteins; Image Processing, Computer-Assisted; Indoles; Lymph Nodes; Lymphatic System; Macromolecular Substances; Mice; Mice, Transgenic; Microscopy, Confocal

PubMed: 26077718
DOI: 10.1084/jem.20142290

Authors: Jerrah K Holth, Sarah K Fritschi, Chanung Wang...

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Topics: Amyloid beta-Peptides; Animals; Brain; Circadian Rhythm; Extracellular Fluid; Female; Male; Mice; Mice, Transgenic; Sleep; Sleep Deprivation; Wakefulness; tau Proteins

PubMed: 30679382
DOI: 10.1126/science.aav2546

Authors: Ian F Harrison, Ozama Ismail, Asif Machhada...

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.

Topics: Alzheimer Disease; Animals; Aquaporin 4; Brain; Cerebrospinal Fluid; Disease Models, Animal; Extracellular Fluid; Glymphatic System; Mice; Mice, Inbred C57BL; Mice, Transgenic; tau Proteins

PubMed: 32705145
DOI: 10.1093/brain/awaa179

Review

Authors: Angelika Chachaj, Kazimierz Gąsiorowski, Andrzej Szuba...

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Pathological deposits of neurotoxic proteins within the brain, such as amyloid-ß and hyperphosphorylated tau tangles, are the prominent features in AD. According to recent studies, the newly discovered brain lymphatic system was demonstrated to be crucial in the clearance of metabolic macromolecules from the brain. Meningeal lymphatic vessels located in the dura mater drain the fluid, macromolecules, and immune cells from cerebrospinal fluid (CSF) and transport them, as lymph, to the deep cervical lymph nodes. The lymphatic system provides the perivascular exchange of CSF with interstitial fluid (ISF) and ensures the homeostasis of neuronal interstitial space. In this review, we aim to summarize recent findings on the role of the lymphatic system in AD pathophysiology and discuss possible therapeutic perspectives, targeting the lymphatic clearance mechanisms within the brain.

Topics: Humans; Alzheimer Disease; Brain; Lymphatic System; Glymphatic System; Extracellular Fluid

PubMed: 35410605
DOI: 10.2174/1570159X20666220411091332

Review

Authors: Wen-Tao Liu, Yu-Peng Cao, Xiao-Han Zhou...

Living things comprise a typical hierarchical and porous medium, and their most fundamental logical architectures are interstitial structures encapsulating parenchymal structures. The recent discovery of the efficient transport mechanisms of interstitial streams has provided a new understanding of these complex activities. The substance transport of interstitial streams follows mesoscopic fluid behavior dynamics, which is intimately associated with material transfer in nanoconfined spaces and a unique signal transmission. Accordingly, the evaluation of interstitial stream transport behavior at the mesoscopic scale is essential. In this review, recent advances in physical and chemical properties, the substance transport model, and the characterization methods of interstitial streams at the mesoscopic scale, as well as the relationships between interstitial streams and disease are summarized. Interstitial stream transport can be used as a basis to fully mine hierarchal behavior in images to expand imaging behavior into an omics field. By starting from the perspective of soft matter, a new understanding can be gained of health and disease and quantitative physical markers for research, clinical diagnosis, and treatment can be provided, as well as prognosis evaluation in complex diseases such as cancer and Alzheimer's disease. This will provide a foundation for the development of medicine of soft matter.

Topics: Cardiovascular Diseases; Chronic Disease; Extracellular Fluid; Humans; Hydrodynamics; Neoplasms; Neurodegenerative Diseases

PubMed: 34978164
DOI: 10.1002/advs.202100617

Authors: Mark R Sullivan, Laura V Danai, Caroline A Lewis...

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

Topics: Animals; Cell Line, Tumor; Extracellular Fluid; Female; Heterografts; Male; Metabolomics; Mice, Inbred C57BL; Neoplasms; Nutrients; Plasma; Tumor Microenvironment

PubMed: 30990168
DOI: 10.7554/eLife.44235

Review

Authors: Jianming Xiang, Ya Hua, Guohua Xi...

Fluid homeostasis is fundamental for brain function with cerebral edema and hydrocephalus both being major neurological conditions. Fluid movement from blood into brain is one crucial element in cerebral fluid homeostasis. Traditionally it has been thought to occur primarily at the choroid plexus (CP) as cerebrospinal fluid (CSF) secretion due to polarized distribution of ion transporters at the CP epithelium. However, there are currently controversies as to the importance of the CP in fluid secretion, just how fluid transport occurs at that epithelium versus other sites, as well as the direction of fluid flow in the cerebral ventricles. The purpose of this review is to evaluate evidence on the movement of fluid from blood to CSF at the CP and the cerebral vasculature and how this differs from other tissues, e.g., how ion transport at the blood-brain barrier as well as the CP may drive fluid flow. It also addresses recent promising data on two potential targets for modulating CP fluid secretion, the Na/K/Cl cotransporter, NKCC1, and the non-selective cation channel, transient receptor potential vanilloid 4 (TRPV4). Finally, it raises the issue that fluid secretion from blood is not constant, changing with disease and during the day. The apparent importance of NKCC1 phosphorylation and TRPV4 activity at the CP in determining fluid movement suggests that such secretion may also vary over short time frames. Such dynamic changes in CP (and potentially blood-brain barrier) function may contribute to some of the controversies over its role in brain fluid secretion.

Topics: Extracellular Fluid; TRPV Cation Channels; Brain; Blood-Brain Barrier; Cerebral Ventricles; Choroid Plexus

PubMed: 37209923
DOI: 10.1016/j.nbd.2023.106159

Authors: Pradnya P Samant, Megan M Niedzwiecki, Nicholas Raviele...

Tissue interstitial fluid (ISF) surrounds cells and is an underutilized source of biomarkers that complements conventional sources such as blood and urine. However, ISF has received limited attention due largely to lack of simple collection methods. Here, we developed a minimally invasive, microneedle-based method to sample ISF from human skin that was well tolerated by participants. Using a microneedle patch to create an array of micropores in skin coupled with mild suction, we sampled ISF from 21 human participants and identified clinically relevant and sometimes distinct biomarkers in ISF when compared to companion plasma samples based on mass spectrometry analysis. Many biomarkers used in research and current clinical practice were common to ISF and plasma. Because ISF does not clot, these biomarkers could be continuously monitored in ISF similar to current continuous glucose monitors but without requiring an indwelling subcutaneous sensor. Biomarkers distinct to ISF included molecules associated with systemic and dermatological physiology, as well as exogenous compounds from environmental exposures. We also determined that pharmacokinetics of caffeine in healthy adults and pharmacodynamics of glucose in children and young adults with diabetes were similar in ISF and plasma. Overall, these studies provide a minimally invasive method to sample dermal ISF using microneedles and demonstrate human ISF as a source of biomarkers that may enable research and translation for future clinical applications.

Topics: Biomarkers; Child; Extracellular Fluid; Humans; Hydrogels; Needles; Skin

PubMed: 33239384
DOI: 10.1126/scitranslmed.aaw0285

Authors: Ryszard Stefan Gomolka, Lauren M Hablitz, Humberto Mestre...

The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular endfeet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport. Yet, no studies have systematically examined how these abnormalities in structure and water transport correlate with glymphatic function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) along with intravoxel-incoherent motion (IVIM) DWI, while evaluating glymphatic function using a standard dynamic contrast-enhanced MR imaging to better understand how water transport and glymphatic function is disrupted after genetic deletion of AQP4. AQP4 KO mice had larger interstitial spaces and total brain volumes resulting in higher water content and reduced CSF space volumes, despite similar CSF production rates and vascular density compared to wildtype mice. The larger interstitial fluid volume likely resulted in increased slow but not fast MR diffusion measures and coincided with reduced glymphatic influx. This markedly altered brain fluid transport in AQP4 KO mice may result from a reduction in glymphatic clearance, leading to enlargement and stagnation of fluid in the interstitial space. Overall, diffusion MR is a useful tool to evaluate glymphatic function and may serve as valuable translational biomarker to study glymphatics in human disease.

Topics: Mice; Humans; Animals; Glymphatic System; Extracellular Fluid; Brain; Aquaporin 4; Water

PubMed: 36757363
DOI: 10.7554/eLife.82232