Sleep drugs block brains from tau in Alzheimer’s study

A common sleep medication seems to not only help people fall asleep, but it actually protects the brain from destructive damage to Alzheimer’s disease and related diseases.

New research from the University of Washington School of Medicine shows that Lemborexant is a FDA-approved sleep aid that prevents the accumulation of harmful proteins and loss of brain tissue, used in genetically designed mice to develop into symptoms of Alzheimer’s.

The findings published in Natural Neuroscience on May 27 raise an attractive possibility that targeting sleep problems in the early stages of neurodegenerative diseases may slow down or prevent brain damage from leading to memory loss and cognitive decline.

Not just sleep

What is particularly striking about this study is that lemborexant not only improves sleep, but also actively protects brain tissue. Mice receiving the drug showed that hippocampus volume was 30% to 40% larger than untreated animals, and hippocampus was crucial for memory formation. These protective effects are specifically specific to lemborexant without Zolpidem (another sleeping drug that works through different brain pathways).

“We have long known that sleep loss is a risk factor for Alzheimer’s disease,” Barbara Burton and Reuben M. “In this new study, we show that lemborexant improves sleep and reduces abnormal TAU, which seems to be the main driver of neurological damage we see in Alzheimer’s disease and several related diseases.”

The study focused on TAU, a protein that usually helps maintain brain cell structure. But when tau is abnormally modified (too many chemical tags called phosphate groups), it brings inflammation together, triggers inflammation and kills neurons. This process occurs not only in Alzheimer’s disease, but also in progressive supranuclear paralysis, cortical disease syndrome and certain frontotemporal dementia.

How drugs work

Lemborexant belongs to a novel sleeping drug called a dual Orexin receptor antagonist. With older sleep targeting the brain’s calming system, these drugs can work by blocking Olexanoate protein, a protein that keeps us awake and alert. By turning off these “wake” signals, the drug can make natural sleep more likely to occur.

But the researchers discovered something unexpected. The benefits of this medication seem to be more than just improving sleep quality. When they examined brain tissue from treated mice, they found that abnormally phosphorylated TAU levels were significantly reduced, a toxic form that caused brain damage. The drug appears to prevent Tau from picking up too many chemical tags in the first place, keeping it healthy, functional.

This protective effect appears to function through specific cellular pathways involving cyclic adenosine monophosphate (CAMP) and protein kinase A (PKA). When Lemborexant blocks the Orexin receptor, it reduces the activity of the pathway, thus preventing the hyperphosphorylation that makes Tau toxic.

Sleep brain connection

The relationship between sleep and Alzheimer’s disease has been attracting attention in recent years. Poor sleep quality and sleep disorders often occur several years before other dementia symptoms are obvious. Previous studies by Holtzman’s team and others have shown that sleep deprivation can increase levels of amyloid plaques and tau tangles, two iconic proteins in Alzheimer’s disease.

What is unclear is whether improving sleep can really prevent or reverse this damage. The new study suggests that at least in the case of pathology associated with TAU, it may be possible.

The researchers used genetically modified mice to develop tau accumulation within two months and tested lemborexant. The animals receiving the drug not only slept better, but also showed brain inflammation, reduced synaptic connections between neurons, and maintained a larger brain mass in key memory areas.

Confusing gender differences

One of the most interesting findings of the study is that protection occurs only in male mice. Female animals showed improved sleep but did not reduce brain damage, a pattern that surprised the researchers and highlighted the complex ways in which gender affects neurodegeneration.

Holtzman speculated that this difference may be related to observations of female mice in this particular model, resulting in severe damage associated with tau. “The damage was reduced from the beginning, and the potential beneficial effects of the drug may be smaller and harder to detect,” he explained.

This gender difference emphasizes the importance of studying men and women in neurodegenerative disease research and suggests that treatments may require different tailoring for men and women.

Clinical significance

Although these results are promising, it is recommended to recommend Lemborexant to prevent Alzheimer’s disease in humans. The study was conducted in mice with genetic susceptibility to tau accumulation, and it is not clear whether similar benefits will occur in age-related neurodegenerative people.

Furthermore, the study involved providing drugs to mice before brain damage occurs. Whether Lemborexant can help people who already have important TAU ​​pathology remains to be tested.

However, these findings add to the growing evidence that sleep interventions may play a role in a comprehensive approach to preventing neurodegenerative diseases. Current Alzheimer’s treatments are primarily targeting amyloid plaques and offer modest benefits only in slowing down cognitive decline.

“The antibodies we use to treat amyloid in early-stage, mild Alzheimer’s patients are helpful, but they don’t slow down the disease as we want,” Holtzmann noted. “We need methods to reduce abnormal TAU accumulation and its accompanying inflammation, and this type of sleep aid deserves further investigation.”

expect

The research team is planning additional studies to better understand the mechanisms behind Lemborexant’s protective effects and to explore whether combining different treatments is more effective than any one treatment alone.

The main findings of the study include:

• In treated male mice, lemborexant reduced abnormal TAU phosphorylation by about 50%
• In treated animals, the brain tissue volume of key memory areas is 30-40% larger
• Drugs reduce inflammation markers and retained synaptic connections
• Need to specifically block the benefits of Orexin receptors, not just to improve sleep
• In this particular disease model, the effect is limited to male mice

The study represents a collaboration between University of Washington researchers and Eisai, a pharmaceutical company that develops Lemborexant. Although the drug has been approved for treatment of insomnia, these findings suggest that it may have broader therapeutic potential to characterize neurodegenerative diseases characterized by TAU pathology.

For those who are concerned about Alzheimer’s risk, the study reinforces the importance of maintaining healthy sleep patterns, although it is too early to prevent Lemborexant from preventing neurodegeneration. As our understanding of sleep-brain connections continues to evolve, it is becoming clear that good night’s rest is probably one of the most powerful tools for maintaining brain health throughout our lives.