School of Medicine

Protein involved in removing Alzheimer’s buildup linked to circadian rhythm

Fractured sleep, daytime sleepiness and other signs of disturbance in one’s circadian rhythm are common complaints of people with Alzheimer’s disease, and the problems only get worse as the disease progresses. But the reason for the link between Alzheimer’s and circadian dysfunction is not well understood.

Researchers at Washington University School of Medicine in St. Louis say that a clue may lie in the brain protein YKL-40. In a study published Dec. 16 in Science Translational Medicine, the researchers report that YKL-40 is both regulated by clock genes and involved in clearing away potentially toxic buildup of Alzheimer’s proteins in the brain. Moreover, Alzheimer’s patients who carry a genetic variant that reduces YKL-40 levels maintain their cognitive faculties longer than people without the variant, the scientists found.

The findings suggest that YKL-40 is a possible link between circadian rhythm dysfunction and Alzheimer’s, and that therapies targeting the protein may slow the course of the disease.

“If your circadian clock is not quite right for years and years — you routinely suffer from disrupted sleep at night and napping during the day — the cumulative effect of chronic dysregulation could influence inflammatory pathways such that you accumulate more amyloid plaques,” said senior author Erik Musiek, MD, PhD, associate professor of neurology. Amyloid plaques in the brain are one of the early hallmarks of Alzheimer’s disease. “We hope that a better understanding of how the circadian clock affects YKL-40 could lead to a new strategy for reducing amyloid in the brain.”

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.

Although circadian dysfunction affects many aspects of health and disease, it is most easily detected as sleep disturbances, 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, even those in the earliest stage of the disease, when amyloid plaques have begun forming but cognitive symptoms have not yet appeared.

Musiek, whose work has long focused on the link between circadian rhythm and neurodegenerative diseases such as Alzheimer’s, was conducting a screen for genes regulated by the circadian clock when one specific gene caught his eye.

“The gene for YKL-40 came up as highly regulated by clock genes,” Musiek said. “That was really interesting because it is a well-known biomarker for Alzheimer’s.”

About a decade ago, David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, and Anne Fagan, PhD, professor of neurology, discovered that high levels of YKL-40 in the cerebrospinal fluid are a sign of Alzheimer’s. Subsequent research by Fagan and others revealed that YKL-40 levels rise with normal aging and as Alzheimer’s progresses.

Musiek, first author Brian V. Lananna, then a graduate student, and colleagues set out to explore the connection between the circadian clock, YKL-40 and Alzheimer’s. The disease is characterized by chronic inflammation, so the researchers investigated how the presence or absence of a key circadian gene affects non-neuronal brain cells under inflammatory conditions. They discovered that the clock dictates how much YKL-40 is made.

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