-
Molecular Neurodegeneration Aug 2023Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in... (Review)
Review
Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients. Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD. Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the CNS, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating CNS fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD.
Topics: Animals; Humans; Alzheimer Disease; Amyloid beta-Peptides; Genome-Wide Association Study; Meninges; Lymphatic System; Brain; Mammals
PubMed: 37580702
DOI: 10.1186/s13024-023-00645-0 -
Stroke Mar 2022Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent...
BACKGROUND
Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent neuroinflammation. The meningeal lymphatic system is responsible for clearance of macromolecules and pathogenic substances from the central nervous system; however, its role in intraparenchymal hematoma clearance and ICH outcomes is unknown. In the present study, we aimed to understand the contribution of the meningeal lymphatic system to ICH pathologies and to test whether pharmacological enhancement of meningeal lymphatic function promotes hematoma resolution and brain recovery after ICH.
METHODS
Immunofluorescence of whole-mount meninges was used to measure complexity and coverage level of meningeal lymphatic vasculature following ICH induction. Fluorescent microbeads and PKH-26-labeled erythrocytes were used to evaluate drainage function of the meningeal lymphatic system. Visudyne treatment, deep cervical lymph node ligation, and VEGF (vascular endothelial growth factor)-C injection were performed to manipulate meningeal lymphatic function. Neurobehavioral performance and hematoma volume were assayed by the cylinder test and histological measurements. Iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were assessed by immunohistochemistry and antibody-based fluorescence staining.
RESULTS
Meningeal lymphangiogenesis and enhanced lymphatic drainage occurred during the late phase of ICH. Ablation and blockage of meningeal lymphatic vessels impeded hematoma clearance, whereas pharmacological enhancement of their function reduced hematoma volume, improved behavioral performance, and reduced brain residual erythrocytes, iron deposition, neuronal loss, and astroglial activation.
CONCLUSIONS
Early enhancement of meningeal lymphatic function is beneficial for ICH recovery. Targeting the meningeal lymphatic system is therefore a potential therapeutic approach for treating ICH.
Topics: Animals; Brain; Cerebral Hemorrhage; Cilostazol; Lymphangiogenesis; Lymphatic System; Male; Meninges; Mice; Neurons; Neuroprotective Agents
PubMed: 35144488
DOI: 10.1161/STROKEAHA.121.037834 -
Nature Immunology Nov 2020Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies...
Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates.
Topics: Animals; Anxiety; Behavior, Animal; Cell Proliferation; Cerebral Cortex; Disease Models, Animal; Dura Mater; Gene Expression Profiling; Gene Expression Regulation; Interleukin-17; Meninges; Mice; Mice, Knockout; Neurons; Receptors, Antigen, T-Cell, gamma-delta; Signal Transduction; T-Lymphocyte Subsets; Transcriptome
PubMed: 32929273
DOI: 10.1038/s41590-020-0776-4 -
Annual Review of Immunology Apr 2020Neuroimmunology, albeit a relatively established discipline, has recently sparked numerous exciting findings on microglia, the resident macrophages of the central... (Review)
Review
Neuroimmunology, albeit a relatively established discipline, has recently sparked numerous exciting findings on microglia, the resident macrophages of the central nervous system (CNS). This review addresses meningeal immunity, a less-studied aspect of neuroimmune interactions. The meninges, a triple layer of membranes-the pia mater, arachnoid mater, and dura mater-surround the CNS, encompassing the cerebrospinal fluid produced by the choroid plexus epithelium. Unlike the adjacent brain parenchyma, the meninges contain a wide repertoire of immune cells. These constitute meningeal immunity, which is primarily concerned with immune surveillance of the CNS, and-according to recent evidence-also participates in postinjury CNS recovery, chronic neurodegenerative conditions, and even higher brain function. Meningeal immunity has recently come under the spotlight owing to the characterization of meningeal lymphatic vessels draining the CNS. Here, we review the current state of our understanding of meningeal immunity and its effects on healthy and diseased brains.
Topics: Animals; Central Nervous System; Disease Susceptibility; Homeostasis; Humans; Immunity; Lymphatic Vessels; Meninges; Neuroimmunomodulation; T-Lymphocyte Subsets
PubMed: 32340575
DOI: 10.1146/annurev-immunol-102319-103410 -
Biomolecules May 2022There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main... (Review)
Review
There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.
Topics: Animals; Brain; Central Nervous System; Cerebral Small Vessel Diseases; Glymphatic System; Humans; Lymphatic System; Meninges
PubMed: 35740873
DOI: 10.3390/biom12060748 -
Acta Neurologica Belgica Apr 2021A spinal subdural hygroma is a rare entity. In this review, we try to contribute to the pooling of current knowledge about spinal subdural hygroma, from embryology and... (Review)
Review
A spinal subdural hygroma is a rare entity. In this review, we try to contribute to the pooling of current knowledge about spinal subdural hygroma, from embryology and physiology until radiological detection and treatment. The relevant articles in the literature regarding spinal subdural hygroma were reviewed, using a sensitive search strategy on Internet databases. A spinal subdural hygroma is associated with trauma, iatrogenic causes, spontaneous intracranial hypotension headache, and probably meningitis. MR imaging is the golden standard for diagnosis. Treatment of the hygroma is almost always conservative and surgery is seldom necessary, however treating the underlying cause is important. The physiology, in spite of numerous suggestions and hypotheses in literature, remains unclear. The prevalence of spinal subdural hygroma is also still unknown. Only a few articles deal with spinal subdural hygroma, because it is an uncommon entity, without specific symptoms. Probably it is often not diagnosed because of the frequent association with other cranial or spinal pathologies and the need for high-resolution imaging. More research is required to examine the prevalence, importance, and pathophysiology of spinal subdural hygroma.
Topics: Blood Patch, Epidural; Cerebrospinal Fluid Leak; Humans; Intracranial Hypotension; Magnetic Resonance Imaging; Meningitis; Spinal Cord Injuries; Subdural Effusion
PubMed: 33393068
DOI: 10.1007/s13760-020-01558-1 -
Nature Nov 2020The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain...
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.
Topics: Aged; Aging; Animals; Blood-Brain Barrier; Cranial Sinuses; Female; Fungi; Gastrointestinal Microbiome; Germ-Free Life; Humans; Immunoglobulin A, Secretory; Intestines; Male; Meninges; Mice; Mice, Inbred C57BL; Plasma Cells
PubMed: 33149302
DOI: 10.1038/s41586-020-2886-4 -
Nature Medicine Mar 2021Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD)....
Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.
Topics: Disease Progression; Drainage; Humans; Lymphatic Vessels; Magnetic Resonance Imaging; Meninges; Parkinson Disease; alpha-Synuclein
PubMed: 33462448
DOI: 10.1038/s41591-020-01198-1 -
Magnetic Resonance in Medical Sciences... Mar 2022The central nervous system (CNS) was previously thought to be the only organ system lacking lymphatic vessels to remove waste products from the interstitial space.... (Review)
Review
The central nervous system (CNS) was previously thought to be the only organ system lacking lymphatic vessels to remove waste products from the interstitial space. Recently, based on the results from animal experiments, the glymphatic system was hypothesized. In this hypothesis, cerebrospinal fluid (CSF) enters the periarterial spaces, enters the interstitial space of the brain parenchyma via aquaporin-4 (AQP4) channels in the astrocyte end feet, and then exits through the perivenous space, thereby clearing waste products. From the perivenous space, the interstitial fluid drains into the subarachnoid space and meningeal lymphatics of the parasagittal dura. It has been reported that the glymphatic system is particularly active during sleep. Impairment of glymphatic system function might be a cause of various neurodegenerative diseases such as Alzheimer's disease, normal pressure hydrocephalus, glaucoma, and others. Meningeal lymphatics regulate immunity in the CNS. Many researchers have attempted to visualize the function and structure of the glymphatic system and meningeal lymphatics in vivo using MR imaging. In this review, we aim to summarize these in vivo MR imaging studies and discuss the significance, current limitations, and future directions. We also discuss the significance of the perivenous cyst formation along the superior sagittal sinus, which is recently discovered in the downstream of the glymphatic system.
Topics: Animals; Brain; Central Nervous System; Glymphatic System; Magnetic Resonance Imaging; Meninges
PubMed: 33250472
DOI: 10.2463/mrms.rev.2020-0122 -
Developmental Cell Jul 2020The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that...
The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single-cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid, and pia. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial subpopulation marked by the expression of μ-crystallin. Developmental analysis reveals a progressive, ventral-to-dorsal maturation of telencephalic meninges. Our studies have generated an unparalleled view of meningeal fibroblasts, providing molecular profiles of embryonic meningeal fibroblasts by layer and yielding insights into the mechanisms of meninges development and function.
Topics: Animals; Brain; Crystallins; Fibroblasts; Humans; Meninges; Mice; Mice, Inbred C57BL; RNA-Seq; Single-Cell Analysis; Transcriptome
PubMed: 32634398
DOI: 10.1016/j.devcel.2020.06.009