Ultrastructure of the brain waste-clearance pathway

Abstract

Efficient metabolic waste clearance is essential for optimal brain function. Waste accumulation can cause inflammation, tissue damage, and potentially lead to dementia and other neurological disorders. The primary waste exit route is debated, with evidence suggesting the lymphatic system or arachnoid villi/granulations as possible pathways. This study uses an ultrastructural dataset to emphasize the potential underestimation of macrophages and arachnoid villi/granulations in waste removal. The glymphatic system and neurovascular unit play crucial roles in this process, but their precise involvement is unclear. Based on brain surface ultrastructure analysis, waste clearance may occur through a transcellular route involving astrocytes to the perivascular space. Waste is then either phagocytosed by perivascular macrophages or directed to the subarachnoid space for meningeal macrophage phagocytosis. Evidence is provided that macrophages transport non-degradable waste in lysosomes to arachnoid villi for exocytosis into the villus lumen and venous system routing. Additionally, the study investigates fibroblast-macrophage interactions via primary cilia, potentially optimizing waste clearance. The role of astrocytes in brain water homeostasis and GFAP's potential significance in water filtration are also examined. This study offers valuable insights into waste clearance mechanisms in the brain, potentially aiding dementia understanding and treatment.

Microglia contact cerebral vasculature through gaps between astrocyte endfeet

“…Furthermore, perivascular fibroblasts (PVFs) and perivascular macrophages (PVMs) are found on large ascending venules, penetrating arterioles, and first-order capillaries, with some processes reaching third-order capillaries, but are rarely found elsewhere on the vascular tree. 4, 27…”

“…5 were made by annotations in Neuroglancer, extracting coordinates from the JSON file, followed by adding meshes to the resulting point clouds using Meshlab and finally 3D rendering in Blender, as previously described. 27…”

“…5 were made by annotations in Neuroglancer, extracting coordinates from the JSON file, followed by adding meshes to the resulting point clouds using Meshlab and finally 3D rendering in Blender, as previously described. 27 Microglia were identified as previously described. 4,12 In brief, they were identified by their small soma size compared to other cell bodies, their distinct heterochromatin pattern, thin cytoplasm, prominent dark lysosomes (visible at low magnification), and an elongated irregular shape that often resembles a bean 22, 23 (Fig.…”

Aligning with the predecessors and counterarguments: A systematic review of the anatomical correlates for the newly discovered meningeal layer in the existing literature

“…TEM-based validation of the SLYM and exploration of its detailed ultrastructure remains a concern. Although only a few TEM studies that examined this are currently available, none explicitly supported SLYM’s independent existence (Grubb, 2023; Mapunda et al, 2023; Pietilä et al, 2023). Grubb recently analyzed publicly available electron microscopy datasets for mice brains (Grubb, 2023).…”

“…Although only a few TEM studies that examined this are currently available, none explicitly supported SLYM’s independent existence (Grubb, 2023; Mapunda et al, 2023; Pietilä et al, 2023). Grubb recently analyzed publicly available electron microscopy datasets for mice brains (Grubb, 2023). The author described the arachnoid mater as composed of at least four different cell types: the dural border cells, ABCs, reticular cells, and inner arachnoid fibroblasts.…”