Structural characterization of SLYM—a 4th meningeal membrane

Fluids and Barriers of the CNS, Год журнала: 2023, Номер 20(1)

Опубликована: Дек. 14, 2023

Abstract Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, classification of connective meningeal membranes surrounding brain is based on postmortem macroscopic examination. Ultrastructural single cell transcriptome analyses have documented that layers can be subdivided into several cellular characteristics. We here re-examined existence a 4 th membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging freshly resected whole brains showed covers entire stem forms roof shielding subarachnoid cerebrospinal fluid (CSF)-filled cisterns pia-adjacent vasculature. Thus, strategically positioned to facilitate periarterial influx produced CSF thereby support unidirectional glymphatic transport. Histological analysis that, spinal cord parts dorsal cortex, fused with barrier layer, while basal typically formed 1–3 layered membrane subdividing space two compartments. However, great care should taken when interpreting organization delicate leptomeningeal tissue sections. show hyperosmotic fixatives dehydrate risk shrinkage dislocation these fragile preparations.

Язык: Английский

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Improving drug delivery to the brain: the prodrug approach

Expert Opinion on Drug Delivery, Год журнала: 2024, Номер 21(5), С. 683 - 693

Опубликована: Май 3, 2024

Introduction The prodrug approach has been thought to be a simple solution improve brain drug delivery for decades. Nevertheless, it still comes as surprise that there is relatively little success in the field. best example anti-parkinsonian levodopa serendipitously discovered transporter-utilizing brain-delivered rather than rationally developed one.

Язык: Английский

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Emergence of the brain-border immune niches and their contribution to the development of neurodegenerative diseases

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Май 28, 2024

Historically, the central nervous system (CNS) was regarded as ‘immune-privileged’, possessing its own distinct immune cell population. This privilege thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid (BCSFB), which prevented crossing of peripheral cells their secreted factors into CNS parenchyma. However, recent studies have revealed presence in proximity various brain-border niches such choroid plexus, cranial bone marrow (CBM), meninges, perivascular spaces. Furthermore, emerging evidence suggests that may able infiltrate brain through these sites play significant roles driving neuronal death pathology progression neurodegenerative disease. Thus, this review, we explore how contribute pathogenesis disorders Alzheimer’s disease (AD), Parkinson’s (PD), multiple sclerosis (MS). We then discuss several options for harnessing neuroimmune potential improve prognosis treatment debilitative using novel insights from studies.

Язык: Английский

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Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 26, 2024

Abstract Although the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem this class drugs. Here, we report an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) brain delivery amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in mouse model deposition. Asymmetrical Fc mutations (ATV cisLALA ) allowed molecule to selectively retain effector function only when bound Aý while mitigating TfR-related hematology liabilities. Mice treated with ATV :Aý exhibited broad parenchymal distribution; contrast, anti-Aý IgG was highly enriched at arterial perivascular spaces where vascular localizes likely plays role induction ARIA. Importantly, : almost completely eliminated inflammation associated treatment. Taken together, has potential improve both efficacy immunotherapy through enhanced biodistribution mediated by across blood-brain barrier.

Язык: Английский

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Advances and controversies in meningeal biology

Nature Neuroscience, Год журнала: 2024, Номер unknown

Опубликована: Сен. 27, 2024

Язык: Английский

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Single-nucleus transcriptome profiling provides insights into the pathophysiology of adhesive arachnoiditis

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2025, Номер unknown, С. 167655 - 167655

Опубликована: Янв. 1, 2025

Язык: Английский

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Evidence for cellular and solute passage between the brain and skull bone marrow across meninges: A systematic review

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Янв. 25, 2025

A potential two-way passage of cells and substances between the brain skull bone marrow may open for new insights into neurological disease. The arachnoid membrane was traditionally considered to restrict larger molecules in CSF from entering dura directly. However, data on exchange have recently emerged. Here, we conducted a systematic literature answer question: What is current evidence regarding movement marrow, spanning meninges? We excluded studies related head or trauma, cranial fractures defects, cancer invasion, leakage, spontaneous intracranial hypotension, spinal mater, solely focusing meningeal lymphatic vessels vessels. review identified 16 that provide communication brain, meninges marrow. Cells (such as B T neutrophils), bacteria, (tracers, drug compounds) been reported pass bone. most are performed rodents, emphasizing need translation humans.

Язык: Английский

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Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 29, 2025

Язык: Английский

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Cerebral Venous Blood Flow Regulates Brain Fluid Clearance via Meningeal Lymphatics

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

The vascular system regulates brain clearance through arterial blood flow and lymphatic drainage of cerebrospinal fluid (CSF). Idiopathic intracranial hypertension (IIH), characterized by elevated pressure dural venous sinus stenoses, can be treated restoring via stenting, suggesting a role for in clearance. Using magnetic resonance imaging (MRI) IIH patients healthy controls, we identified that stenoses were associated with impaired drainage, perivenous retention, accumulation. To investigate this further, developed mouse model bilateral jugular vein ligation (JVL), which recapitulated key human findings, including hypertension, calvarial regression, swelling due to further dissect the respective roles meningeal vessels clearance, performed JVL mice depletion. These exhibited spontaneous pressure, but did not exacerbate effect. Moreover, synchronous restoration lymphatics observed after was absent lymphatic-deficient mice.Transcriptomic analyses revealed remodeling induced driven VEGF-C signaling between mesenchymal endothelial cells. findings establish sinuses as critical platform where interacts cells preserve integrity function, essential

Язык: Английский

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The sentinel against brain injury post-subarachnoid hemorrhage: efferocytosis of erythrocytes by leptomeningeal lymphatic endothelial cells

Theranostics, Год журнала: 2025, Номер 15(6), С. 2487 - 2509

Опубликована: Янв. 20, 2025

Rationale: The clearance of extravasated erythrocytes represents the most reasonable strategy against brain injury post-subarachnoid hemorrhage (SAH). There is little knowledge about autologous post-SAH. leptomeningeal lymphatic endothelial cells (LLECs) have been less studied functionally, which were firstly harvested and cultured in vitro by our group previously are probably related to post-SAH for they closely surround subarachnoid space. Methods: We established a SAH animal model, employed primary LLECs vitro, mimicked conditions performed RNA sequencing, transfected with adenovirus adeno-associated virus both vivo reveal molecular mechanisms efferocytosis its neuroprotection Results: Firstly, we demonstrated eryptosis-initiated degradation vitro. Furthermore, found preferentially adhered engulfed apoptotic while sparing from intact erythrocytes, suggesting their novel capacity erythrocytes. Additionally, plays role on via improving neurological functions, maintaining neurostructural integrity, alleviating neuropathological consequences During efferocytosis, phosphatidylserine (PS) receptor (PSR) mediated recognition LLECs. also confirmed that NHL repeat-containing 2 (NHLRC2) positively regulated serve as central regulator it Conclusions: This study elucidated subsequently These findings highlight prompt, efficient, regulable pathway performs sentinel

Язык: Английский

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