A new study suggests that a protein in the brain may link Alzheimer’s disease with abnormal circadian rhythms, indicating a future therapeutic goal to slow the course of the disease.
Researchers at Washington University School of Medicine in St.Louis say that one of the evidence for the link between Alzheimer’s disease and daily dysfunction may lie in the brain protein YKL-40.
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In the study, published Dec.16 in the journal Science Translational Medicine, researchers report that YKL-40 is regulated by circadian rhythm genes and is involved in removing the potentially toxic buildup of Alzheimer’s proteins in the brain.
Moreover, the team found that Alzheimer’s patients who carry a variant that lowered YKL-40 levels maintained their cognitive abilities longer than people without the variant.
Lead author of the study, Eric Musick, MD, associate professor of neurology, said: “If your biological clock has been disturbed for years and years, so that you routinely suffer from sleep disruption at night and nap during the day, then the cumulative effect of chronic dysregulation can affect “On inflammatory pathways so that more amyloid plaques accumulate (one of the hallmarks of Alzheimer’s disease). Hopefully, a better understanding of how the circadian rhythm affects YKL-40 will lead to a new strategy for reducing amyloid in the brain.”
Our daily rhythms are controlled by a master clock in the brain that is driven by the day and night cycle. Each cell also maintains its own internal clock, linked to the master clock. A surprisingly wide range of biological processes, from sugar absorption to body temperature, to immune and inflammatory responses, varies depending on the time of day.
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Although the weakness of the biological clock affects many aspects of health and disease, it is easy to detect from sleep disorders, such as difficulty falling asleep or staying asleep at night and increased sleepiness during the day. Such problems are common in people with Alzheimer’s disease, even those who are in the first stage of the disease, when amyloid plaques begin to form but cognitive symptoms have not yet appeared.
Dr. Musick, whose work has long focused on the link between circadian rhythms and neurodegenerative diseases such as Alzheimer’s, was examining genes regulated by the biological clock when a specific gene caught his attention.
“The YKL-40 protein was shown to be highly regulated by clock genes. This was really interesting because it is a known biological marker of Alzheimer’s disease,” he said.
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The researchers conducted experiments on models of mice with Alzheimer’s disease prone to developing amyloid plaques, and genetically modified a number of them to lack YKL-40, while another group remained unmodified.
Once the mice were eight months old (that is, they became old by the rat’s standards), the researchers examined the animals’ brains.
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They found that amyloid-exposed mice without YKL-40 developed only about half the amount of amyloid compared to those animals carrying the protein.
The amyloid plaques are usually surrounded by immune cells called microglia that help prevent the plaques from spreading. And in mice lacking YKL-40, microglia were more abundant and more apt to consume and remove amyloid.
“It is possible that this YKL-40 protein modifies the level of activation of microglia in the brain. And when you get rid of the protein, it seems that the microglia is more active to eat up the amyloid. It’s a subtle thing, a modification in the system, but it seems sufficient to reduce Significant total burden of amyloid.
The team concluded that the YKL-40 protein speeds up the pathogenesis of Alzheimer’s disease, possibly by altering the glial function in the brain.
The researchers explained that when removing the protein, the microglia appeared to be more active to eat up amyloid.
The team suggests that the YKL-40 protein produced by the Chi3l1 gene could be identified as a potential therapeutic target for slowing the progression of Alzheimer’s disease, and provides insight into the regulation of neuritis by astrocyte circadian rhythms (the largest and most important glial cells).
Source: medicalxpress
