Discovery of a Link Between Circadian Rhythm and Alzheimer’s May Offer a New Target for Treatment

    By Kathleen Berger, Executive Producer for Science & Technology

    Circadian rhythm is the natural process that helps control your daily schedule for sleep and wakefulness. The circadian clock regulates the sleep-wake cycle, repeating itself on each rotation of the Earth, roughly every 24 hours. Fractured sleep, daytime sleepiness and other signs of disturbance in circadian rhythm are common complaints of people with Alzheimer’s disease, and the problem gets worse as the disease progresses.

    “The circadian clock controls when we sleep and if you don’t sleep enough, you can accumulate this protein called amyloid beta in the brain that forms these amyloid plaques which we think are the first hallmark of Alzheimers Disease,” said Erik Musiek, MD, PhD, is an associate professor of neurology at Washington University School of Medicine in St. Louis.

    Musiek’s lab made a discovery about the circadian clock gene Chi3l1.  He said Chi3l1 encodes the protein YKL-40, which is a biomarker for Alzheimer’s disease.

    About a decade ago in the Department of Neurology at Washington University, researchers discovered that high levels of YKL-40 in the cerebrospinal fluid are a sign of Alzheimer’s disease. Subsequent research revealed that YKL-40 levels rise with normal aging and as Alzheimer’s progresses.

    Now armed with knowledge about the circadian clock gene Chi3l1 regulating YKL-40, Musiek’s lab investigated the role of YKL-40 in the brain using a mouse model. Through animal studies, the researchers concluded YKL-40 plays a role in the toxic buildup of amyloid plaques in the brain, providing a link between circadian rhythm dysfunction and   Alzheimer’s disease. The discovery may provide a new target for Alzheimer’s therapies.

    “To investigate the role of what YKL-40 is possibly doing in the disease, we took a mouse model of beta amyloidosis. So what that means is the mice get amyloid beta plaques in a similar way humans get amyloid beta plaques, ” explained first author Brian V. Lananna, PhD, postdoctoral fellow, then graduate student. “We took these mice and we deleted the Chi3l1 gene, which means they don’t create any YKL-40 protein. When we take away YKL-40, we found that those mice developed plaques at a slower rate, which suggests YKL-40 is perhaps playing detrimental role in the progression of amyloid beta plaques.”

    Alzheimer’s Disease is characterized by chronic inflammation. So the researchers used their mouse models to closely observe the role YKL-40 has on immune cells, called microglia.

    “Sometimes microglia can play a beneficial role in Alzheimer’s disease by eating away the amyloid beta plaques, but they can also sometimes produce more inflammatory factors,” said Lananna.

    “We think YKL-40 serves as a brake, to keep microglial activation and inflammation under control,” said Musiek. “But in doing so it may suppress the ability of these cells to eat up this amyloid beta in these plaques. We think if you have too much YKL-40 around, it may prevent the microglia from properly taking up a beta and removing these plaques.”

    Musiek said his study goes along with another study involving 778 Alzheimer’s patients through the Knight Alzheimer’s Disease Research Center at Washington University School of Medicine. Researchers discovered 26% of study participants carried a genetic variant that reduces levels of YKL-40. In the Alzheimer’s patients with the genetic variant, cognitive skills declined a slower rate.

    The research from Musiek’s lab offers hope that therapies targeting the YKL-40 producing gene, Chi3l1, which is linked to the circadian clock, may slow the course of Alzheimer’s disease. But a lot of work would need to be done to make sure the approach is both safe and effective.

    “It’s possible that if you have a drug that lowers the levels of YKL-40 in the brain, it could promote microglia and their ability to eat up these amyloid plaques, but that still has to be proven,” said Musiek. “We envision it as if you could treat people before they have symptoms and help to eliminate these plaques from their brain, that they could maybe never develop the disease or develop a much milder case later in life.