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

Image credit BRIAN LANANNA

Immune cells known as microglia (turquoise with red dots) surround a plaque of the Alzheimer’s protein amyloid (blue). The red dots indicate that the microglia are prepared to remove the potentially damaging plaque. Researchers at Washington University School of Medicine in St. Louis have discovered a protein that links the amyloid-removal process to the circadian clock. The protein, YKL-40, could help explain why people with Alzheimer’s frequently suffer from sleep disturbances, and provide a new target for Alzheimer’s therapies.

Brain protein helps explain link between circadian rhythm, Alzheimer’s disease

by Tamara Bhandari•December 16, 2020

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, an 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. Read more at: https://medicine.wustl.edu/news/protein-involved-in-removing-alzheimers-buildup-linked-to-circadian-rhythm/

Study:

Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis

By Brian V. Lananna, Celia A. McKee, Melvin W. King, Jorge L. Del-Aguila, Julie M. Dimitry, Fabiana H. G. Farias, Collin J. Nadarajah, David D. Xiong, Chun Guo, Alexander J. Cammack, Jack A. Elias, Jinsong Zhang, Carlos Cruchaga, Erik S. Musiek

Science Translational Medicine 16 Dec 2020

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