The Latest on Nature: Recreating controversy? Scientists have revealed that the leak of the young blood-brain barrier is more serious.

Learn about the latest progress in neuroscience ● click the blue word to pay attention to us ● the blood-brain barrier in the brain is equivalent to setting a "travel restriction barrier" in the brain and peripheral blood - limiting some molecules, ions and other substances in the blood into the brain.this level plays a key role in protecting the brain from harmful substances in the peripheral blood.coins have two sides. The protection of blood-brain barrier limits the entry of drugs to a certain extent.previous studies have shown that the permeability of blood-brain barrier increases with age.but now this conclusion is challenged.on July 1, 2020, Tony Wyss Coray, a professor of Neuroscience at Stanford University and an expert in gerontology, published an article in the journal Nature on July 1, 2020. It was found that the protein in peripheral blood entered the brain much faster in young people than before, and found that the infiltration of this protein decreased with age (1).who is Tony Wyss Coray? In fact, his legend mainly lies in the proposal of "exchange blood for anti-aging". In 2014, their research team injected plasma from young mice into old mice, which enhanced the cognitive ability of old mice and delayed aging (2), which caused a great sensation at that time.however, in subsequent studies, it was found that such exchange transfusion did not actually delay aging (3).therefore, "exchange transfusion anti-aging" is in dispute.some studies believe that the blood-brain barrier is static, but in fact it is in dynamic change and is moving.the heart pumps out about 70ml of blood each time. Therefore, in the process of each heartbeat, the endothelial cells and ependymal cells of the brain will have close contact with various proteins in the blood, so it is inevitable that some life activities such as signal transduction and protein transportation will occur.the picture is quoted from document 1, where plasma protein is unscrupulously entered into the brain. The researchers labeled the plasma protein and injected it into young and old mice respectively to track the dynamic changes of protein in peripheral blood in the brain in this way.20 hours later, a large number of these labeled plasma proteins were Co located with neurons and microglia in the brain of healthy young mice, that is to say, the plasma proteins infiltrated into the brain of healthy adult mice through the blood-brain barrier.in addition, plasma protein intake was not the same in different types of blood vessels: the highest uptake was in venous vessels, the lowest was in arterial vessels, and between the two in capillaries.therefore, the transport of plasma protein increases with the decrease of vascular pressure.in order to further explore the underlying mechanism, the researchers studied the correlation between gene expression and plasma protein uptake by cerebral endothelial cells by single cell sequencing technology, and found that the expression of this associated gene is mainly the signal pathway of protein transport mediated by vesicles.in fact, in this single cell experiment, the researchers only briefly talked about the participation of signaling pathway from the macroscopic aspect. one possibility is that researchers have discovered a lot of useful information here, and the new research results of Tony Wyss Coray may be seen in subsequent studies. what is more surprising is that more plasma proteins enter young mice than into old mice, which contradicts the current popular increase in plasma protein permeability after aging. the researchers finally found that the difference between the two is mainly reflected in how endothelial cells transport these proteins. in young adult mice, specific proteins bind to plasma membrane receptors on endothelial cells. these receptors are integrated into vesicles and transported through endothelial cells - a process known as receptor mediated endocytosis. in aged mice, receptor-mediated endocytosis was significantly reduced, but non receptor mediated (nonspecific) endocytosis was increased, resulting in nonspecific plasma protein entry into the brain (4). in fact, there are some structural changes during the transition of this age-related exocytosis in young and old mice, mainly manifested by the decrease of pericyte coverage in old mice. researchers hope to find a target gene to restore receptor-mediated exocytosis in aged mice. This gene should meet five conditions: 1. Specific genes of blood-brain barrier; 2. Genes expressed on the surface of endothelial cells; 3. Up regulated genes with aging; 4. Genes related to plasma protein uptake; 5 FDA approved molecular inhibitors. alkaline phosphatase (Alpl) gene has become the most potential target. Alpl did not fail to live up to the expectations of researchers. Small molecule Alpl inhibitors promoted the uptake of plasma protein in the brain of aged mice, but had no effect on young mice. these results suggest that inhibition of Alpl, a negative regulator of age-related blood brain transport, promotes receptor-mediated endocytosis. in general, this paper refreshes the cognition of blood-brain barrier again - the blood-brain barrier of young mice infiltrates more protein in peripheral blood, and further reveals the mechanism. in fact, this controversy on the understanding of blood-brain barrier, to a certain extent, shows that our understanding of blood-brain barrier is not enough. This controversy will promote the research of blood-brain barrier and develop in doubt. References: 1. Physiological blood – brain transport is impaired with age by a shift in transpytosis, 2. Villeda, S. A et al. Young blood reverses age related impairments in cognitive function and synaptic plasticity in mice. Nature medicine, 659–663 (2014)3.  Justin Rebo et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature Communications, 2016; 7: 13363 4. Young brains welcome protein，