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SSpecialists have shown that giving blood from an old mouse to a young mouse or vice versa induces a kind of "Freaky Friday" effect: the brains of young mice exposed to old blood lose their vitality, while young blood rejuvenates certain brain functions the older mice.
However, what they do not know is what causes these transformations. On Monday, scientists reported that they had attached to a protein made by blood vessels as a key player in how ancient blood appears to cause cell damage in the brain.
In addition, they found that disabling the protein in aged mice improved the function of their brain cells and the performance of these mice on cognitive tests. Their study, published in the journal Nature Medicine, indicates that the protein, called VCAM1, could be a potential target in the treatment of neurocognitive disorders.
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As humans and mice age, brain cells called microglia – a type of immune cell in the nervous system – become more active and produce neuroinflammation. At the same time, the activity of neural stem cells, involved in the manufacture of more neurons, is compressed. Together, these two changes are thought to play a key role in the structural and functional deterioration that occurs with age.
The injection of blood from an old mouse into a young mouse triggers these same cellular responses to aging, suggesting that some plasma factors – the liquid and high-protein part of the blood – signal that these changes are occurring in the brain. But unlike other organs, a healthy brain is isolated from the blood by a barrier, leaving open the question of how blood components can influence what happens in the brain.
"What was completely misunderstood, is how circulating factors in the blood can communicate given that we have an intact blood brain barrier," said Hanadie Yousef, the main author of the blood-brain barrier. article, which led the study as a postdoctoral researcher at Stanford.
For the study, Yousef and his colleagues turned to the endothelial cells of the brain, the ones that make up the blood vessels that cross the brain. They focused on the cells of the hippocampus, a region of the brain essential to learning and memory. They hypothesized that these cells, which contribute to the formation of the blood-brain barrier, could serve as intermediaries in the interactions between the two camps. And when they looked at the levels of different proteins in people as they got older, they discovered that the one that increased the most over time was VCAM1, which is manufactured and found on the surface of these endothelial cells.
Endothelial cells throughout the body express the VCAM1 protein, which causes immune cells to circulate in the blood and escort them into damaged or injured tissue. Their directive is different in the endothelial cells of the brain. Here they attach immune cells in the same way, but these cells can not enter the brain because of the barrier. But through different signals, this link always triggers the immune response of the brain.
The researchers however noted that an excess of VCAM1 could be a sign of a brain in decline or be involved. In a study of nearly 700 older people, one team found that higher levels of VCAM1 correlated with more severe cognitive impairment.
In the new mouse study, researchers dismantled VCAM1 in two ways to determine whether high levels of protein contributed to cognitive impairment or simply a byproduct of aging.
First of all, they deleted the gene (called VCAM-1which codes for the protein and found that these mice were protected against the effects of the transferred aged blood.
They also blocked VCAM1 with an antibody, leaving the immune cells in the blood unable to bind to the endothelial cells. These older mice had more neuronal stem cell activity and reduced microglial activity than untreated older mice, demonstrated improved cognitive measures and solved a labyrinth test as well. was acting of spring chickens.
"In older mice, if we give them anti-VCAM1 or deleted VCAM-1 For most of their lives, it blocks the harmful effects of this aged plasma, "said Tony Wyss-Coray, professor of neurology and neurological sciences at Stanford and lead author of the article.
The researchers do not know exactly what is happening, but they suggest that some older plasma components favor the expression of VCAM1. With more VCAM1 on the surface of the endothelial cells, the immune cells are more attached to the blood-brain barrier. This in turn produces signals that promote inflammation and other cellular – and possibly cognitive – problems associated with aging.
Julie Andersen, a neuroscientist at the Buck Institute, who was not involved in the work, said that she thought it was significant that Stanford researchers had identified something in the endothelial cells that seems to be involved in the mechanisms of aging. Often, she said, research tends to neglect these cells.
She posed however the question of whether the process described in the paper could be just one way in which aging carries the brain. If, for example, the blood-brain barrier starts to "run away" a little over time – if it allows cells or proteins that should not exist to enter the brain – then it could be another process of aging that hurts the brain. Just targeting VCAM1 may not be able to overcome this problem, and other ways of worsening time reduce brain health.
"It is clear that it is a potential mechanism that may play a role in the impact you see on microglial activation and the reduction of stem cell proliferation, but I would say that in the aging, there are other factors that could be at stake here, "said Andersen. . "But I think it's good that they've identified a marker of endothelial cells that changes with age and proposed a viable hypothesis to explain how the increase in this marker could be the cause of some of these age-related phenomena, and how the use of an antibody can restore some of the changes. "
Yousef has completed his post-doctorate and is now CEO of Juvena Therapeutics, a startup in the tissue regeneration sector. But Wyss-Coray and his lab are still trying to find out more about VCAM1. They also began to investigate whether blocking with an antibody was effective in animal models of vascular dementia.
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