Written by Joyce Smith, BS. This study demonstrated YKL-40 is both regulated by clock genes and involved in clearing away the potentially toxic build-up of Alzheimer’s disease (AD) proteins in the brain and that AD patients who carry a genetic variant that reduces YKL-40 levels maintain their cognitive faculties longer than those individuals without the variant.
Neuroinflammation plays a critical role in the pathogenesis of most neurodegenerative diseases, including Alzheimer’s disease (AD) 1,2, thus the regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer’s disease (AD). YKL-40 is an excreted astrocytic glycoprotein encoded by the gene Chi3l1 and although Chi3l1/YKL-40 is a human cerebrospinal fluid (CSF) biomarker of neuroinflammation, its role in the progression of AD remains unknown. Chi3l1/YKL-40 is elevated in AD 3,4 and other neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis and dementia 5-7. Along with tau and other markers of inflammation and neurodegeneration it increases during the aging process and can be used to predict disease progression 3,4. Signs of the body’s disrupted circadian rhythm such as interrupted sleep and daytime sleepiness and napping are common complaints among people with AD. These sleep issues increase with disease progression, and yet, to date, the association between AD and circadian dysfunction has not been clarified.
In a current 2020 study 8, Musiek and colleagues found that AD participants who carried the genetic variant Chi3l1 had reduced YKL-40 levels, maintained their cognitive faculties longer than those who lacked the variant, and that the Chi3l1 gene for YKL-40 was not only regulated by clock genes but was also involved in clearing away the potentially toxic build-up of Alzheimer’s Aß proteins in the brain. The researchers examined data on AD participants that was collected as part of several ongoing longitudinal observational studies of aging and dementia carried out at the Knight Alzheimer’s Disease Research Center. Their objective was to determine whether the genetic variant, CHI3l1, that reduces CSF YKL-40 levels, might influence the rate of AD progression. They found that Alzheimer’s patients who carry the Chi3l1 variant maintained their cognitive faculties longer than patients who lack the variant. A quarter (26%) of the AD participants who were carriers of the genetic variant Chi3L1 had the progression of their AD lowered by 16% (P = 0.031). The team then sought to explore the mechanisms by which CHI3l1/YKL-40 might alter AD pathogenesis, including glial activation, in both in vivo and in vitro mouse models. Lastly, they investigated how Chi3l1 expression was regulated by the circadian clock, using a variety of tissue-specific Bmal1 KO mice, and other circadian clock gene mutant mice.
In both the mice and cell studies, researchers demonstrated that deleting the gene variant Chi3LL reduced the inflammatory responses, increased the removal of astrocyte and microglial Aß, and decreased amyloid plaque formation in the brain, thus validating that the CHI3L1 gene variant, which decreases CSF YKL-40 concentrations in humans, also slows down the progression of AD. (AD mice who lacked the YKL-40 gene developed less amyloid and had more immune cells available to remove it compared to the control mice who carried gene). Evidence from the mice studies also revealed that the circadian clock in astrocytes strongly regulates Chi3l1 transcription and how much YKL-40 is produced. Collectively, the results suggest that Chi3l1/YKL-40 slows down the pathogenesis of AD and highlights an association between glial circadian clocks and Chi3l1 expression.
Linking the amyloid-removal process to the circadian clock could help explain why people with Alzheimer’s frequently suffer from sleep disturbances. Hopefully, through a better understanding of how the circadian clock affects the YKL-40, the protein will become a new target for Alzheimer’s therapies and lead to a new strategy for reducing amyloid in the brain.
Source: Lananna, Brian V., et al. “Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis.” Science Translational Medicine 12.574 (2020).
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
Posted February 23, 2021.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
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