The older you get, the stronger the brain barrier? Nature uncovers age-related changes in the blood-brain barrier.

Blood brain barrier (BBB) is the barrier between brain and blood circulation system, and its permeability is low.it is generally believed that the integrity of BBB is necessary to maintain brain function.then, does BBB's penetration of some exogenous tracers completely represent the level of barrier and transport function? On July 1, 2020, Tony Wyss Coray research group of Stanford University Medical School published the latest results online in nature. The study found that with the increase of age, the physiological transport function of BBB weakened, and its uptake of plasma protein decreased.it is not completely closed, it not only plays the role of barrier, but also has transport, immune and other functions.every time the heart beats, BBB is impacted by blood.this process may lead to local transport, signal transduction and other events.after fluorescent labeling a variety of endogenous plasma proteins, we found that endogenous circulating proteins can penetrate into healthy brain under physiological conditions.Image Source: nature to explore the mechanism of BBB transporting plasma protein, the authors sequenced the single cell RNA of endothelial cells, and linked the uptake level of each endothelial cell with the gene expression profile.after analysis, it was found that there was a gradient in the uptake of plasma protein by endothelial cells of arteriovenous trees.its transport increased with the decrease of vascular pressure, and its uptake was the most in vein.Image Source: nature. Subsequently, the authors combined the published transcriptome data of cerebral endothelial cells for enrichment analysis, and the results showed that the receptor-mediated transport function (RMT) was defective.moreover, with the increase of age, the transport of brain endothelial cells gradually changed from ligand specific RMT to nonspecific vesicular transport.Image Source: the authors also quantified the changes of reticulin and vesicles with age by high-resolution microscopy of microvessels stained with antibodies.they found that there were more cytoreticular proteins in young mice and more vesicles in older mice.this result confirmed that non-specific endocytosis increased and receptor-mediated specific endocytosis decreased with age.Image Source: nature by assessing the changes of vascular density, astrocyte coverage and pericyte coverage with age, the authors found that there were pericyte deletion, ectopic calcification and dysfunction in BBB of normal aging mice.these changes were accompanied by CO localization of type I collagen and Alpl (a negative transport regulator). accordingly, the authors used Alpl inhibitors for further study. the results showed that after Alpl inhibition, the plasma absorption of aging brain parenchymal cells increased except transferrin. in general, the authors found the age-related changes of plasma protein infiltration in BBB and elucidated its possible mechanism, and demonstrated the role of Alpl in aging related BBB function changes. these findings reveal the mechanism of physiological protein transport in healthy brain and the mechanism of age-related blood-brain barrier dysfunction, which is helpful for clinical selection of more efficient drug delivery methods. end reference: [1] physical blood – brantranport is imported with age by a shift in transcytosis