Drugs targeting the biological clock may help treat Alzheimer’s disease

ST. LOUIS — Regular sleep disruptions take a toll on the body’s circadian rhythm, a key part of our biological clock that regulates the sleep-wake cycle in individuals. A study by researchers at Washington University shows that a protein produced by circadian rhythm genes is linked to Alzheimer’s disease. Scientists believe that the debilitating disease could thus be treated with a drug that targets the body clock.

The protein, known as YKL-40, sheds fresh light on the link between bad sleep, daytime drowsiness, and dementia. “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,” explains senior author Dr. Erik Musiek, an associate professor of neurology, in a statement. “Our data suggest that in Alzheimer’s, it’s bad. People who have less of it fare better.”

The finding, published in Science Translational Medicine, is based on older mice engineered to develop misfolded proteins that clump together and cause Alzheimer’s. Mice with a mutation preventing YKL-40 forming had half as many amyloid plaques, a tell-tale sign of the disease. They had more immune cells called microglia that consume and remove the neuron killers.

“This YKL-40 protein probably serves as a modulator of the level of microglial activation in the brain. 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,” says Musiek. “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.”

Circadian rhythm may influence Alzheimer’s risk more than amyloid plaques

An analysis of genetic data from 778 people taking part in aging and dementia studies at the university backed up the results. Cognitive skills declined 16 percent slower in the one in four (26 percent) who carried a variant that reduces levels of YKL-40.

The protein is part of a fiendishly complex biological cycle which makes us sleepy and then wakes us up. Fractured sleep, napping, and other signs of disturbances are common complaints of people with Alzheimer’s, which worsen as the disease progresses.

The study suggests a YKL-40 destroying medication would slow its course. “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,” says Musiek.

Amyloid plaques begin occurring years before the devastating symptoms of confusion and memory loss. “We hope a better understanding of how the circadian clock affects YKL-40 could lead to a new strategy for reducing amyloid in the brain,” Musiek adds.

A “master clock” in the brain keeps our body in sync with the world around it to make us sleepy at night. It uses light to help keep track of time. Each cell also maintains a linked internal clock, helping control functions ranging from sugar absorption to body temperature to immune and inflammatory responses.

Musiek was screening genes they regulated when a specific one caught his eye. “The gene for YKL-40 came up as highly regulated by clock genes. That was really interesting because it is a well-known biomarker for Alzheimer’s,” he explains.

A decade ago, another Washington team discovered high levels in cerebrospinal fluid are a sign. It was subsequently revealed they rise in normal aging – and Alzheimer’s. Now Professor Musiek and colleagues have found the clock dictates how much YKL-40 is made. He said: “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.”

SWNS writer Mark Waghorn contributed to this report.

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