A Washington University neurology lab is working to understand how the brain works with our natural sleep-wake patterns — and what that could mean for progression and prevention of disease. 

As hundreds of researchers across the country work to find cures for common neurodegenerative conditions, such as Alzheimers, scientists at WashU are joining in the fight. 

Dr. Erik Musiek’s lab, for example, is studying how the brain adapts to circadian rhythms, which is our body’s process of adapting to night and day.   

“Almost all of our bodily functions have some rhythm to be in tune with [the] 24-hour turning of the earth,” Musiek said. 

In particular, Musiek’s lab has studied a variety of what they call “clock control genes,” which are genes that are assumed to be controlled by “the clock,” or the body’s circadian rhythm. One such gene, Chi3l1, seems to be especially important in processes of disease and neurodegeneration. 

Musiek said that the discovery of the Chi3l1 gene was almost accidental — and illustrated “the beauty of being at WashU.”  

At the time, Musiek’s lab was disrupting the mechanics of the circadian rhythm in rodent models, and the Chi3l1 gene kept popping up. 

Dr. David Holtzman, an esteemed Alzheimer’s researcher and Musiek’s mentor, published a paper well over a decade prior looking at the biomarkers of Alzheimer’s patients. Among other things, they found elevated levels of a protein called YKL- 40 in the spinal fluid of Alzheimer’s patients — a result replicated by many other labs since then. The gene that encoded that protein? Chi3l1. 

“It took me a little while to put those two things together,” Musiek said. “We probably should have known right away, but sometimes the genes and the proteins have different names.” 

Musiek then found that if they deleted Chi3l — a clock-controlled gene — in rodent models, they developed less amyloid plaque in their brains, protecting them against Alzheimer’s pathology. 

Dr. Holtzman’s lab was one of a few containing WashU scientists to link sleep disruption and Alzheimer’s disease progression. Now, a couple of other WashU researchers, such as Dr. Brendan Lucey and Dr. Yo-El Ju, are diving deeper into the mechanics of sleep and neurodegeneration. Musiek is attacking another, related question — how does circadian rhythm regulate neurodegeneration? 

“Sleep” and “circadian rhythm” are terms people tend to think of as interchangeable, but they aren’t necessarily the same thing.

“The circadian clock is really mediated by this molecular machinery, whereas sleep is a behavioral state,” Musiek said. For example, you can mess up your sleep without damaging your circadian rhythms, but if you mess up your circadian rhythms, it will disrupt your sleep. 

“One of the main things we see in patients is when they start to get Alzheimer’s disease, they’ll start to have a fragmentation of their sleep-wake cycle,” Musiek said. “They tend to sleep more during the day and tend to wake up more at night. And so it’s still unclear if that’s a circadian-rhythm problem or it’s a sleep problem — or both.” 

Another chicken-or-egg problem that Musiek has to consider is whether Alzheimer’s affects circadian rhythms or vice versa. 

“It definitely looks as though the pathology of the plaques and tangles can disrupt your circadian rhythms in your sleep,” Musiek said. “But then the question is, what if you have poor circadian rhythms when you’re 40 years old — does that mean you’re going to be at risk for Alzheimer’s disease later on?” 

Most recently, Musiek’s lab posted a pre-publication of a paper that looked at a new, but related query that could relate to neurodegeneration, as increased inflammation in the brain has been associated with Alzheimer’s pathology. 

The question was simple: does the time of day affect how leaky the blood-brain barrier becomes when inflammation is present? Jennifer Lawrence, a PhD student in Musiek’s lab, worked to figure out that in mice, the blood-brain barrier is more susceptible to pathogens during the evening compared to the morning due to differing light exposure. 

Aside from impacts on neurodegeneration, the experiment’s findings could be useful when considering the timing of medical procedures. Musiek said the study could inform when and how to do surgery or administer neurological medication. 

“If the brain has these ebbs and flows in inflammation and we can understand the mechanism of that, we can leverage that to keep the brain in whatever state we want,” Musiek said. 

Despite a growing body of evidence that suggests it’s important to adhere to your circadian rhythm to fight disease and inflammation, Musiek said it’s difficult for the public to follow healthy habits. 

“In theory, you really shouldn’t have a lot of really bright light exposure after about eight or nine o’clock at night because that [can] screw up your circadian clock,” he said. “It’s a horrible time in human history as far as circadian health goes because we’ve got giant TVs, we have LED lights…” 

And Musiek said his nighttime routine isn’t necessarily better than the average person’s. He’s pretty busy, managing his lab, a patient schedule, and a family. 

“I don’t have the greatest sleep habits,” he admitted. “And, probably, most of my colleagues don’t either, to be honest.”