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Role Identified for Brain Protein Regulated by Circadian Clock Genes in Clearing Toxic Build-up in Alzheimer’s Disease

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Studies by a research team at Washington University School of Medicine in St. Louis indicate that a brain protein known as YKL-40 may link Alzheimer’s disease with dysfunction in circadian rhythms, suggesting that treatments that target the protein could slow the course of the disease. Their work, reported in Science Translational Medicine, found that YKL-40 is both regulated by clock genes and involved in clearing away the potentially toxic build-up of Alzheimer’s proteins in the brain. The team’s studies indicated that Alzheimer’s patients who carry a genetic variant that reduces YKL-40 levels maintain their cognitive faculties longer than those individuals without the variant.

“People have been measuring YKL-40 in spinal fluid for several years, but we were never sure of its function, if it was good or bad,” said Erik Musiek, MD, PhD, an associate professor of neurology. “Our data suggest that in Alzheimer’s, it’s bad. People who have less of it fare better. If you could design a therapy to lower YKL-40, it might help the microglia remove more amyloid and maybe slow the progression of disease.” Musiek is senior author of the researchers’ paper, which is titled, “Chi3l1/YKL-40 is controlled by astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis.”

Our daily rhythms are set by a master clock in the brain that is driven by the day and night cycle. Each cell also maintains its own internal clock, pegged to the master clock. A surprisingly broad array of biological processes—from sugar absorption to body temperature to immune and inflammatory responses—vary by time of day. Fractured sleep, daytime sleepiness, and other signs of disturbance in the body’s circadian rhythm are common complaints among people with Alzheimer’s disease, and the problems only get worse as the disease progresses. However, to date, the reason for this link between Alzheimer’s and circadian dysfunction hasn’t been well understood.

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