Nature breaks the textbook: Lots of blood-borne proteins enter the young, healthy brain!

, July 2, 2020 /PRNewswire/bio-valley -- Blood-carrying proteins enter the brains of younger, healthy mice more than older mice, a finding that will change our understanding of the blood-brain barrier and how it changes with agethe properties of the cerebrovascular vessels limit their penetration of blood-derived ions, molecules and cellsThe blood-brain barrier (BBB) is essential for normal nerve function and protection from damage to the brain, but it is also a major obstacle to drug deliveryIt has been suggested that BBB becomes more permeable as it gets older, but Yang and others have found something completely different in the journal NatureThey show that the blood-brain barrier allows blood-borne proteins to enter the healthy brain much faster than previously thought, and that the amount of plasma protein swarmed into the brain actually decreases with ageThe work could help researchers understand how the brain responds to the system's protein signals and the role of the blood-brain barrier in age-related cognitive declineThis may also improve the way drugs enter the brainblood-brain barrier is sometimes considered a static, insurmountable barrierIn fact, it has many dynamic properties -- physical, transport, immunity, and so on -- which closely control the movement of molecules between the blood and the brain, thus controlling the brain's molecular environmentA key question is, what substance can pass through BBB?Yang and others solved the problem by studying how proteins found in plasma enter the brainPrevious studies have tracked the movement of injected exogenous proteins, which are not inherent in the organism, while Yang and colleagues labeled endogenous mouse plasma proteins and injected them back into miceIn this way, they were able to track the movement of proteins that normally interact with the blood-brain barrier in miceThey found that in healthy young adult mice, there were far more plasma proteins entering the brain than previously thought, and therefore it was possible to interact with neural circuitsThe findings suggest that a variety of neural functions, including mood and behavior, can be regulated by system protein signalsfurther experiments showed that in older mice, the amount of plasma protein that penetrated the brain was lower than in younger mice This is surprising because several studies using exogenous tracers have shown that the permeability of the blood-brain barrier increases with age and highlights this increase as a factor contributing to the decline in age-related cognitive ability Yang et al showed these seemingly different results by revealing age-related changes in the transport of proteins through BBB vascular endothelial cells In young adult mice, the main methods of transport include specific proteinbinding endothelial cell receptors These receptors enter the vesicles and transport them to cells, a process known as receptor-mediated transcell swallowing In older mice, receptor-mediated transcellular action decreased significantly, while non-receptor-mediated (nonspecific) transcellular action increased, resulting in more plasma protein nonspecificization into the brain Previous studies using exogenous molecules may have measured only nonspecific extracellular effects, thus ignoring the process by which the vast majority of plasma proteins penetrate into the young brain The specificity of protein entry decreases with age, a finding that may indicate that aging alters the brain's ability to receive specific plasma protein signals photo source: Nature
To understand the mechanism by which the blood-brain barrier transports proteins, Yang and others developed a way to correlate plasma protein intake levels in each endothelial cell with its gene expression spectrum and analyze how the relationship changes along the vascular system This analysis showed that the adsorption of plasma proteins along the vascular network showed a gradient -- the arterial side (blood to the heart, the highest blood pressure) was the smallest, and the venous end was the largest (blood returned to the heart, blood pressure was lowest) Therefore, as the pressure in the blood vessels decreases, the transport of proteinincreases the authors also identified genes in endothelial cells that expresspositive or negative effects on plasma protein intake This list of genes may help identify transcell swallowing receptors that participate in receptor-mediated These receptors may be the target of "Trojan horse" drug releases, where proteins are designed to bind to specific transmembrane receptors that can cross the blood-brain barrier, such as transfideitin receptors As receptor-mediated transcellular action decreases with age, Yang and colleagues' data suggest that the effectiveness of existing Trojan horse methods, such as the method based on transferrous ferritin receptors, also decreases with age But the authors found that the alpl gene's expression increased in endothelial cells in the brains of older mice, while the alpl-encoded protein was pharmacologically inhibited, increasing the transport of receptor-mediated ferritin receptors Therefore, this may be a way to enhance Trojan horse drug delivery, especially for the elderly Yang and his colleagues' findings provide important insights into the penetration of proteins in the brain However, some constraints must be taken into account For example, most of the authors' protein tracking experiments quantified protein penetration into the brain as a whole when it penetrated the brain, but their imaging studies clearly showed significant differences in protein levels in different regions In addition to the blood-brain barrier, the plasma component can also enter the brain through a barrier between blood and cerebrospinal fluid found in the ventricles and the meninges that cover the brain The effect of each barrier on the plasma protein sentry into the brain is not clear It is not known whether proteins enter the entire brain or are confined to specific areas Therefore, the extent to which plasma proteins interact with different neural circuits is not clear in addition, the study did not identify specific proteins that enter the brain It is therefore not clear whether the transport pathway of receptor-mediated affects only a small portion of proteins (such as ferritin and leptin) or a wide range of proteins To identify these proteins, future studies could combine the labeling method used by Yang et al with mass spectrometry-based protein analysis Filling these gaps in our knowledge will be necessary to determine how plasma proteins affect neural circuit function and to use specific barrier mechanisms to guide the delivery of targeted drugs Yang and his colleagues' research also suggest some ways for further research First, it will be critical to understand how age-related changes in proteins entering the brain affect neural circuit function and whether this plays a role in age-related cognitive decline Second, it will be interesting to understand how proteins enter the brain, with factors such as neurological activity, diet, and neurological disorders Third, protein is just a molecule in the blood Using a similar approach to metabolomics, we can identify all the molecules that can enter the brain, which will give us a better understanding of how the blood-brain barrier regulates the neural environment and how it changes with age (BioValleyBioon.com) References: Unexpected amount of blood-borne protein enters the young brain Yang, A.C., Stevens, M.Y., Chen, M.B et al.
Courdi-brain transport is sweed with bya shift in transcytosis.
Nature (2020) https://doi.org/10.1038/s41586-020-2453-z