Perivascular Macrophages Appear Important in Clearance of Molecular Waste from the Brain
Clearance of metabolic waste from the brain falters with age, leading to an increased presence of toxic protein aggregates, such as the amyloid-β associated with Alzheimer's disease, but also others. Evidence has emerged for mechanical issues in the flow of cerebrospinal fluid out of the brain to be important in this contributing cause of neurodegenerative disease. If the cerebrospinal fluid isn't carrying away enough of the metabolic waste, then a garbage catastrophe of one sort or another is the inevitable result. Here, compelling new evidence for one of the many possible deeper causes of those mechanical issues is discussed.
With age, the brain's ability to clear aggregating proteins such as amyloid-β (Aβ) wanes. Researchers have found that the macrophages that cozy up to arteries in the brain help thin out extracellular matrix around these vessels. Macrophages inhabit spaces that border the brain parenchyma, namely along blood vessels and in the meninges. In both locations, they make direct contact with cerebrospinal fluid (CSF). Although these cells have been implicated in conditions such as hypertension, stroke, and Alzheimer's disease (AD), no one knew exactly what they did in healthy brain.
To explore this, researchers killed off border macrophages in wild-type mice by injecting liposomes containing a toxin into the CSF, where they were selectively taken up by macrophages. One week later, researchers injected a fluorescent tracer into CSF at the base of the brain, and tracked its diffusion along vessels. In control mice, arterial pulsing pushed the tracer into parenchyma. In liposome-treated mice, however, it penetrated only half as far as it did in control mice, indicating weaker CSF flow. To see why this was, the authors directly examined arterial movement through a cranial window while they stimulated brain activity by tickling the mice's whiskers. In mice lacking perivascular macrophages, blood vessels dilated less than they did in controls.
Why might this be? Perivascular macrophages are known to pump out matrix metalloproteases (MMPs), which chew up extracellular matrix (ECM) proteins. The authors found that MMP activity around brain blood vessels was suppressed after macrophage depletion, and the ECM was thicker. This overgrowth hindered dilation of blood vessels, in effect making them stiffer. In addition, nearby fibroblasts released more ECM proteins in the absence of macrophages. The authors concluded that macrophages keep vessels supple both by breaking down ECM and via crosstalk with fibroblasts that regulates their output.
Not all perivascular macrophages contribute to CSF flow. An analysis of gene expression revealed two subsets. One expressed the immune marker MHCII, and clustered around veins. Based on their expression profile, the authors believe these cells may recruit circulating leukocytes to brain. The other group expressed LYVE1, a membrane glycoprotein. These cells resided mainly around arteries and arterioles, and were scavengers, engulfing nearby debris. LYVE1 cells seem to be the ones controlling CSF flow, as genetically ablating only this subset thickened ECM and stiffened vessels.
how feasible is a macrophage therapy that stops the ossification of glymphatic system
Also related to alzheimer's and amyloid buildups: https://www.nature.com/articles/d41586-022-03724-2
This does seem to be a hugely important discovery.
"The authors are also exploring whether the decrease in LYVE1 macrophages with age heightens risk for other neurodegenerative disorders. Tal Iram at Stanford University thinks the findings may be generally applicable. "This is a truly novel and exciting new frontier in the study of debris clearance in aging-related diseases … improving CSF flow by targeting macrophages would affect overall clearance of debris, and therefore could be a robust approach for [treating] neurodegenerative disease," she wrote."