Posted on Dec 17, 2020, 6 p.m.
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.
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, Ph.D., 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 the 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. Signs/symptoms 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.
“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 Musiek. 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.”
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 disease, even those in the earliest stage of the disease, when amyloid plaques have begun forming but cognitive symptoms have not yet appeared.
Neuroinflammation plays a critical role in the pathogenesis of most neurodegenerative diseases, including Alzheimer’s disease, and YKL-40, a secreted glycoprotein that is encoded by the gene Chi3l1, is a “well-described human cerebrospinal fluid (CSF) biomarker of neuroinflammation,” which is raised in Alzheimer’s disease, and in other neurologic disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and frontotemporal dementia, the authors explained.
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 the Chi3l1 gene caught his attention. “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, Ph.D., a professor of neurology, discovered that high levels of YKL-40 in the cerebrospinal fluid are a sign of Alzheimer’s disease. Subsequent research by Fagan and others revealed that YKL-40 levels rise with normal aging and as Alzheimer’s progresses. “CSF YKL-40 expression steadily increases with age starting in middle age, even in amyloid-negative individuals,” the authors wrote.
Musiek, study first author Brian V. Lananna, Ph.D., who was then a graduate student, and colleagues, set out to explore the connection between the circadian clock, YKL-40, and Alzheimer’s disease. Given that the disorder is characterized by chronic inflammation 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. “If you have inflammation in the morning, you might get lots of YKL-40; if you get inflammation in the evening, when the clock’s in a different phase, you might get less YKL-40,” Musiek said.
Next, they crossed Alzheimer’s mouse models that are prone to developing amyloid plaques, with either genetically modified mice that lacked the gene for YKL-40, or with unmodified mice, as controls. When the animals reached eight months old—which is elderly for mice—the researchers examined their brains. They found that amyloid-prone mice without YKL-40 only developed about half as much amyloid as those control animals that carried the YKL-40 gene. Amyloid plaques normally are surrounded by immune cells called microglia that help keep the plaques from spreading, and the results also showed that in the mice that lacked YKL-40, these microglia were more plentiful and more primed to consume and remove amyloid, than they were in the control animals.
“Here, we report data from humans and mouse models suggesting that Chi3l1/YKL-40 accelerates AD pathogenesis, potentially by altering glial function in the brain,” the team stated. “We also show evidence from mice that the core circadian clock in astrocytes strongly regulates Chi3l1 transcription and gates its inflammatory induction. Together, our results reveal Chi3l1/YKL-40 as a modulator of AD pathogenesis, and illuminate a link between glial circadian clocks and Chi3l1 expression.” “This YKL-40 protein probably serves as a modulator of the level of microglial activation in the brain,” Musiek said. “When you get rid of the protein, it appears the microglia are more activated to eat up the amyloid. It’s a subtle thing, a tweak in the system, but it seems to be enough to substantially reduce the total amyloid burden.”
Co-author Carlos Cruchaga, Ph.D., a professor of psychiatry, genetics, and neurology, analyzed genetic data from 778 people participating in aging and dementia studies at the university’s Charles F. and Joanne Knight Alzheimer’s Disease Research Center. Their findings showed that about a quarter (26%) of the individuals carried a genetic variant that reduces levels of YKL-40. Cognitive skills declined 16% more slowly in the people with the variant.
“In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression,” the authors wrote. “These data suggest that increases in Chi3l1/YKL-40 that occur during aging and AD may have a detrimental impact on AD pathogenesis by altering glial function and plaque deposition.”
“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,” Musiek said. “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.”
The researchers suggested that their combined findings from mice and human studies “ … identify Chi3l1//YKL-40 as a potential therapeutic target for slowing disease progression in AD and provide insights into the regulation of neuroinflammation by the astrocyte circadian clock.”
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