A drug used to treat insomnia has protected mice against the buildup of the tau protein found to clump abnormally in neurodegenerative diseases like Alzheimer’s. This could lead to new ways to help slow the progress of these diseases.
An increasing number of people are facing cognitive decline personally or in their loved ones. There are almost 10 million new cases of dementia globally each year, and despite decades of research, there are still few treatment options that provide clear benefits.
So due to the links between Alzheimer’s and poor sleep, Washington University neurologist Samira Parhizkar and colleagues investigated a central nervous system depressant, lemborexant, that was approved for use as a sleep aid by the FDA in December 2019.
“We have shown that lemborexant improves sleep and reduces abnormal tau, which appears to be a main driver of the neurological damage that we see in Alzheimer’s and several related disorders,” explains Washington University neurologist David Holtzman.
The role of amyloid beta proteins in Alzheimer’s has been controversial, but they’re not the only proteins implicated in the disease. Tau proteins normally contribute to the structure of brain cells, but past research has linked abnormal ones with the rate of brain atrophy in animal models.
“The antibodies to amyloid that we now use to treat patients with early, mild Alzheimer’s dementia are helpful, but they don’t slow the disease down as much as we would like,” says Holtzman. “We need ways to reduce the abnormal tau buildup and its accompanying inflammation, and this type of sleep aid is worth looking at further.”
But when the researchers compared lemborexant with another sleep aid, zolpidem, the results were unexpected. Mice receiving lemborexant retained up to 40 percent more volume in their memory-forming hippocampus than those who received zolpidem or no sleep aid at all.
“What was surprising was that these effects were not seen with a standard sleep drug like zolpidem, which increases NREM sleep similarly to lemborexant,” Parhizkar told Eric Dolan at PsyPost. “This suggests that the benefit is not just about more sleep, but rather how that sleep is promoted.”
The two sleep drugs work on different mechanisms, and that seems to be key to the protective effects. Lemborexant blocks orexin, a neuropeptide that regulates the sleep cycle, and when the team genetically knocked out orexin receptor 2 in mice, it reduced the buildup of tau in their brains.
Strangely, though, the protective results of lemborexant were only seen in male mice, even though females were also tested. What’s more, mouse studies don’t always produce the same results in humans. Lemborexant has only been approved for short-term use in humans, so its long-term impacts as well as effectiveness in tau reduction still need to be investigated.
While many questions remain to be answered, if the results seen in this study hold true, the researchers hope early intervention with a drug like lemborexant could potentially delay the progression of neurodegeneration.
This research was published in Nature Neuroscience.
