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When we get old, our memory starts to "squeak". The decline in cognitive ability in old age is considered an almost inevitable process, but two studies that were recently done in the laboratory of Prof. Michal Schwartz, from the Neuroven Weizmann Department

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When we get old, our memory starts to "squeak". The decline in cognitive ability in old age is considered an almost inevitable process, but two studies conducted recently in the laboratory of Prof. Michal Schwartz, from the Department of Neurobiology, link the deterioration of brain function to the aging of the immune system. The studies reveal how certain immune cells, located - contrary to all expectations - inside the brain itself, contribute to the health of the central nervous system. The findings show how, over time, the delicate balance in which these cells are found is violated, leading to a new situation - which may impair mental function. These studies may provide clues as to how we can, in the future, slow down or prevent cognitive decline.

For over a decade, Prof. Schwartz has been researching how immune cells moving in the bloodstream help the healing and restoration capacity of the brain, and other parts of the central nervous system. Her research has often challenged the prevailing theories, according to which immune cells cannot enter the brain, and that if they manage to do so, they "infiltrate" through gaps in the set of barriers that protect the brain.

The findings of the first study, recently published in the scientific journal Immunity, show that when the healing immune cells are "delivered" to the brain following an injury, they are not required to escape the barrier system. These cells enter the brain "legally" through a structure called the "choroid plexus", which creates what is known as the "cerebrospinal-fluid barrier". The shell of the blood plexus is the place where the cerebrospinal fluid is created - which is a kind of "shock absorber" that protects the brain tissues. The structures of the blood plexus - one of which is found in each chamber of the brain - contain finger-like extensions, through which, on the one hand, the cerebrospinal fluid is transferred to the brain tissues surrounding the extensions, and on the other hand, plasma and waste materials are evacuated from the brain into the blood vessels.

The members of Prof. Schwartz's research group were surprised to discover that the immune cells enter the central nervous system from this distant structure even when the injury occurs to the spine in a location far from the brain, and that they are not passively swept away from the brain through gaps in the blood-brain barrier, but are mobilized in a controlled manner. The immune cells crossed the cerebrospinal fluid barrier, the buffer between the bloodstream and the brain tissue, and from there they made their way to the site of the damage to the central nervous system. The reason for the surprise was that until now entering the brain was considered "breaking boundaries". "Our findings show that entering the brain through the blood plexus is not breaking boundaries, but entering through a gate that functions like a filter," says Prof. Schwartz. "Immune cells pass through the gate when they are needed. Before that, they are tested, and they are also required to undergo preliminary training, and only the right cells, which have undergone the correct training, are allowed to pass through the gate and enter the blood system."

In the second study, which was published in the Journal of the American Academy of Sciences (PNAS), the scientists sought to accurately identify the type of immune cells that regulate entry into the brain. The scientists identified the immune cells in the blood plexus as a type of T cells specially adapted to the central nervous system, and discovered that a constant supply of these cells is always maintained within the blood plexus. When they meticulously followed the life course of the cells, from young age to old age, the scientists discovered that the disruption of the balance between two chemical substances produced by T cells in the blood plexus, critically affects the properties of the "gate".

One of the substances, called interleukin-4 (IL-4), is known to prevent inflammation and protect brain health. However, paradoxically, when its level rises beyond a certain threshold, it is involved in the production of a substance called CCL11, which is associated, among other things, with cognitive decline. Experiments conducted by the scientists - both in mice and in cell cultures - revealed that in the blood plexus interleukin-4 is usually in equilibrium with another substance, interferon-gamma (IFN-γ). But when the mouse ages, changes that occur in the T cells cause the ratio between the two substances to be disrupted in favor of interleukin-4. The resulting imbalance leads to the development of an inflammatory process and the production of CCL11 by the blood plexus cells. CCL11 penetrates the cerebrospinal fluid and accumulates in the brains of aging mice - as is also the case in humans.

Later, the scientists were able to prevent the process of cognitive deterioration of the old mice through the use of drastic treatment: they "reset" the immune system of the mice through radiation to their bone marrow, and transplanting a new bone marrow. Prof. Schwartz believes that the findings hint at the possibility that in the future it will be possible to restore balance to the brain's immune system with less extreme means. First, the T cells that generate the inflammation, found in the blood plexus in the elderly, are common during aging in other places of the body as well. Therefore, a healing method that would target total damage to cells of this type may be beneficial. Second, the scientists discovered an interesting similarity between the inflammatory process in the brain and asthma. "Asthma is another disease in which a filter is involved - in this case, the airways," says Prof. Schwartz. This similarity also opens the door to treatment options. In addition, the findings of the experiments make it clear that the barriers separating the brain and the immune system are not impenetrable - if only you find the right way to open the gate.

In other words, rather than being considered an inevitable side effect of aging, cognitive decline may one day be a treatable phenomenon, like any other disease of the immune system.

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