Science Sub-Journal Interpretation! Reducing YKL-40 protein expression levels is expected to slow the progression of Alzheimer's disease

December 19, 2020 // --- The symptoms of sleep disruption, daytime drowsiness, and other circadian rhythm disorders are common problems in Alzheimer's patients and will only get worse as the disease progresses.
, the reasons for the association between Alzheimer's disease and circadian rhythm disorders are not clear.
a new study, researchers at Washington University's St. Louis School of Medicine say a clue may lie in the brain protein YKL-40.
report that YKL-40 is both regulated by the clock gene and involved in removing toxic build-ups of potential Alzheimer's proteins in the brain.
, they found that people with Alzheimer's disease who carried a genetic variant that lowered YKL-40 levels spent more time maintaining cognitive abilities than those who did not carry the variant.
published december 16, 2020 in the journal Science Translational Medicine, the paper is titled "Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulations neuroinflammation and Alzheimer's disease pathogenesis."
photo from Science Translational Medicine, 2020, doi:10.1126/scitranslmed.aax3519.
these results suggest that YKL-40 is a possible link between circadian rhythm disorders and Alzheimer's disease, and that treatments that target this protein may slow the progression of the disease.
"If your circadian clock isn't quite right for years--- you're often suffering from nighttime sleep interruptions and daytime naps -- the cumulative effects of chronic disorders can affect the inflammatory pathway, allowing you to accumulate more amyloid plaques," said Dr. Erik Musiek, an associate professor of neurology at the University of Washington's St. Louis School of Medicine and author of the paper.
plaques in the brain are one of the early features of Alzheimer's disease.
to better understand how circadian rhythm clocks affect YKL-40, which may lead to new strategies to reduce amyloid protein build-up in the brain," he said.
" our circadian rhythm is set by the brain's master clock, which is driven by the circadian cycle.
cell also maintains its own internal clock and is hooked to the master clock.
a surprising range of biological processes --- from sugar absorption to body temperature to immune and inflammatory responses--- can vary over time of day.
although circadian rhythm disorders affect many aspects of health and disease, they are most likely to be detected as sleep disorders, such as difficulty falling asleep, or difficulty falling asleep at night, and increased daytime drowsiness.
is common in alzheimer's patients, even in the early stages of the disease.
at this early stage, amyloid plaques have begun to form, but cognitive symptoms have not yet appeared.
Musiek's research has long focused on the link between circadian rhythms and neurodegenerative diseases such as Alzheimer's disease, and he caught his attention when he screened genes that are regulated by circadian clocks.
coding protein YKL-40 is highly regulated by the clock gene," said Musiek, a professor at the time.
's really interesting because it's a well-known biomarker of Alzheimer's disease.
" About a decade ago, Dr. David Holtzman, dean of the Department of Neurology at the University of Washington, and Dr. Anne Fagan, a professor of neurology, discovered that high levels of YKL-40 in cerebrospinal fluid were a hallmark of Alzheimer's disease.
, Fagan et al. found that levels of YKL-40 rise with normal aging and progression of Alzheimer's disease.
Musiek, lead author Dr. Brian V. Lananna and colleagues began exploring the links between circadian rhythm clocks, YKL-40, and Alzheimer's disease.
the disease is characterized by chronic inflammation, the researchers investigated how the presence or absence of a key circadian rhythm gene affects non-neuron brain cells under inflammatory conditions.
they found that circadian rhythm clocks determine the number of YKL-40s manufactured.
Musiek said, "If you have inflammation in the morning, you may get a lot of YKL-40, and if you have inflammation at night, you may get less YKL-40 when the circadian rhythm clock is at a different stage."
" then, the researchers selected models of Alzheimer's mice prone to amyloid plaques and compared them to genetically modified mice that lacked the YKL-40 gene or to mice that had not been genetically modified.
once the mice were 8 months old (by mouse standards, they were old), they examined their brains.
plaques that lack the YKL-40 gene are prone to produce about half as much amyloid in mice that carry the gene.
are surrounded by immune cells commonly referred to as small glial cells and help prevent the plaques from spreading.
in mice lacking YKL-40, small glial cells were richer and more capable of consuming and removing amyloid.
, "This YKL-40 protein may be a regulator of the activation level of glial cells in the brain," musiek said.
when you remove this protein, small glial cells seem to be activated more to devour amyloid.
this is a delicate thing, an adjustment to the system, but it seems to be enough to significantly reduce the total load of amyloid proteins.
" this is consistent with the data in human studies.
, co-author of the paper and a professor of psychiatry at the University of Washington's St. Louis School of Medicine, analyzed genetic data from 778 people who participated in the Alzheimer's Research Center's Aging and Dementia study at the University of Washington.
a quarter (26%) of people carry genetic variants that lower YKL-40 levels.
of people who carried the gene variant declined 16 percent.
Musiek said, "People have been measuring YKL-40 in spinal fluid for years, but we've never been sure what it does, and it's impossible to tell whether it's good or bad."
our data show that in Alzheimer's disease, it's bad.
people who have less of it do better.
if you can design a therapy to reduce YKL-40, it may help small glial cells remove more amyloid, which may slow the progression of the disease.
(Bioon.com) : 1. Brian V. Lananna et al. Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis. Science Translational Medicine, 2020, doi:10.1126/scitranslmed.aax3519.2.Protein involved in removing Alzheimer's buildup linked to circadian rhythm。