According to the schedule
Macrophages that destroy amyloid plaques in Alzheimer's disease work "by the clock"
Alzheimer's disease, which leads to senile dementia, affects millions of people. This neurodegenerative disease characterizes the accumulation of amyloid plaques from a pathological protein in the brain. And recently, when studying the work of immune cells, scientists have discovered a mechanism to enhance this process.
Article by Gretchen T. Clark et al. Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates is published in the journal PLOS Genetics.
A crucial stage in the development of Alzheimer's disease today is considered to be the accumulation of beta-amyloid as a result of a decrease in the brain's ability to utilize this pathological protein. On the other hand, it is known that the development of Alzheimer's disease is associated with a violation of the circadian rhythms (biological clock) of the body, including sleep disorders that can occur years before the symptoms of the disease.
It was found that in healthy people, the content of beta-amyloid in the cerebrospinal fluid fluctuates during the day, but this is not observed in patients with Alzheimer's disease. At the same time, the molecular mechanism underlying the relationship between circadian rhythms and this brain pathology has not yet been studied.
At the molecular level, the work of the internal "biological clock" is controlled by several special proteins that cause cyclic fluctuations of many biological processes with a period of about a day. The patterns associated with such fluctuations are now the subject of intensive study.
It is known that macrophages ("eaters") play an important role in the pathogenesis of Alzheimer's disease. In the early stages of the development of the disease, this role is performed by microglial cells – tissue macrophages based exclusively in the brain. One of the functions of these cells is to serve as "scavengers"; in particular, they destroy beta–amyloid by absorbing it during phagocytosis.
In the later stages of the disease, when neuroinflammation increases, peripheral blood macrophages also begin to migrate to the brain to help microglia. However, the accumulation of amyloid plaques does not stop.
Glial and peripheral macrophages destroy beta-amyloid deposits in the brain in Alzheimer's disease
Earlier, scientists from the Rensselaer Polytechnic Institute (USA) found out which molecules of RNA and cellular proteins of macrophages obey circadian rhythms. Among them were enzymes involved in the biosynthesis of two complex proteins of proteoglycans – heparan sulfate and chondroitin sulfate, located on the cell surface. And recently, researchers have tested the hypothesis that these molecules are the link between the circadian system and Alzheimer's disease.
In a series of experiments using a cell culture of macrophages obtained from the bone marrow of laboratory mice, scientists found that the amount of beta-amyloid consumed by macrophages fluctuates in accordance with the daily rhythm. But if the per gene, one of the main circadian genes, is "turned off" in these immune cells, then this pattern disappears.
When the researchers measured the daily fluctuations in the levels of heparan sulfate and chondroitin sulfate on the surface of macrophages with a normal circadian cycle, they found that the processes of absorption of beta-amyloid and production of proteoglycans in macrophages are in antiphase. At the same time, the complete removal of proteoglycans from the surface of these immune cells enhances their phagocytic activity.
These results suggest that macrophage surface proteoglycans suppress phagocytosis of pathological amyloid protein. Apparently, they contribute to its aggregation and binding on the cell surface, which makes it difficult to absorb and further degrade beta-amyloid already inside the cell.
It can be assumed that in the absence of a circadian rhythm, when the "internal clock" of macrophages "stops" at the production phase of proteoglycans and their phagocytic activity decreases, the removal of pathological amyloid slows down, which contributes to the formation of amyloid plaques. The data obtained can be used to develop methods for stimulating the internal mechanisms of getting rid of beta-amyloid. These results also confirm the importance of healthy sleep to alleviate the symptoms of Alzheimer's disease.
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