Lymphocytes inhibit neurogenesis
Immune cells prevented the neurons of aging mice from multiplying
Perhaps that is why mental abilities decrease with age
Polina Loseva, "The Attic"
A group of researchers from Stanford has disassembled into individual cells a section of the mouse brain in which new neurons are formed. In old mice, among the nerve cells of different specializations, scientists found T-lymphocytes, which are not usually found in the young brain. It turned out that immune cells are aggressive: they multiply and secrete interferon, a pro–inflammatory protein that prevents the precursors of nerve cells from multiplying.
An article on how the immune system affects the brain has been published in Nature, among the authors of which is Stanford scientist Tony Viss-Corey (Dulken et al., Single-cell analysis reveals T cell infiltration in old neurogenic niches). It was his group that demonstrated in 2014 that transfusion of blood from young animals to old ones improves the mental abilities of mice. In 2017, Wiss-Corey and colleagues injected old mice with already human young blood taken from the umbilical cords of newborns, and again, judging by behavioral tests and the number of neural connections in the brain, the condition of the animals improved. Now, among other things, the scientist is conducting clinical studies on blood transfusion from young donors to fight Alzheimer's disease.
In parallel, Wiss-Corey also studies the reverse process – the depressing effect of "old" blood on the brain. This spring, his group showed that after its injections, animals develop signs of inflammation in the vessels of the brain. At the same time, immune cells adhere to the walls of blood vessels and, possibly, secrete pro-inflammatory substances that suppress the work of nervous tissue. In a new paper, Wiss-Corey, as part of a large group of Stanford scientists, looked inside the brains of aging mice.
The researchers conducted a census of the cellular composition of the subventricular zone – the area at the bottom of the ventricle of the brain where new neurons can form, in young (3 months) and old (28-29 months) mice. To do this, scientists extracted this part of the brain, disassembled it into individual cells and sequenced the RNA in each of them, thereby compiling sets of working genes. Using these sets, they identified cellular specialization.
Scientists have found that in the young brain there are many more precursor cells of neurons, that is, those that have not yet found their final "profession" and can multiply. There were practically no such cells in the old brain, but the researchers found a whole population of T-lymphocytes – immune cells designed to find and destroy "broken" cells of the body. At the same time, there were no vessels next to them, which means that the T-cells did not get stuck in the bloodstream, as in previous experiments, but actually made their way inside the nervous tissue.
In the subventricular zone of the brain, T cells (white) are absent, and the precursor cells of neurons (purple) are much more prone to proliferation (green) younger mice (left) than older mice (right). Paloma Navarro, press release Stanford University School of Medicine Immune cells invade aging brains, disrupt new nerve cell formation – VM.
A young healthy brain has its own immune system – microglia. It consists of professional "scavengers" who eat fragments of dead cells and other molecules that disrupt the order in the intercellular substance. Thanks to the blood-brain barrier, no other immune cells can get into the young brain: if they begin to multiply and chase parasites inside the nervous tissue, "peaceful" neurons may die in the process.
Researchers have put forward two hypotheses that can explain the abundance of T-cells in the old brain: either they penetrated through the "leaking" blood-brain barrier, or they came there on purpose, in search of an enemy. To test this, the scientists compared the RNA in brain T-lymphocytes and mouse blood T-lymphocytes. Each T cell is specific, that is, it produces a receptor that recognizes a single molecule. After meeting the target, it begins to multiply, producing a clone of cells with the same receptor. The authors of the article found that the brains of old mice are dominated by T-lymphocytes of several clones, unlike those found in the blood. So, they got there not by chance, but "on business" – probably, some of the old brain cells began to produce "broken" proteins that the immune system took for an enemy.
Finally, the researchers tested how the presence of T-lymphocytes affects the formation of new cells in the brain. The precursor cells of neurons that were grown together with T-lymphocytes divided much worse than those who grew up alone. Apparently, it's about gamma interferon, a pro-inflammatory protein produced by T cells. If you add gamma interferon to the culture medium of the precursors of neurons, then they stop multiplying in the same way as if there was a real lymphocyte next to them.
Thus, Viss-Corey and his colleagues added another touch to the portrait of an aging brain. Inflammation occurs not only in the adjacent vessels, but also directly inside the tissue. And immune cells entering an inflamed organ inhibit cell reproduction in it, which probably exacerbates the age-related decline of the nervous system.
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