Summary: A common sleep medication, lemborexant, may do more than promote rest—it appears to reduce harmful tau buildup and protect the brain from neurodegeneration in mouse models of Alzheimer’s disease.
Source: WUSTL A common sleep aid restores healthier sleep patterns and protects mice from the brain damage seen in neurodegenerative disorders, such as Alzheimer’s disease, according to new research from Washington University School of Medicine in St. Louis.
The drug, lemborexant, prevents the harmful buildup of an abnormal form of a protein called tau in the brain, reducing the inflammatory brain damage tau is known to cause in Alzheimer’s.
In past work studying mice genetically prone to amyloid and tau buildup characteristic of Alzheimer’s disease, they showed that sleep deprivation makes this buildup worse.
In mice genetically prone to harmful tau buildup, lemborexant reduced brain damage compared with control mice.
Lemborexant is a popular sleep aid that may do more than just encourage sleep; in mouse models of Alzheimer’s disease, it seems to lessen damaging tau accumulation and shield the brain from neurodegeneration. In addition to restoring healthier sleep patterns, researchers discovered that this orexin receptor antagonist decreased inflammation and maintained brain structure.
The hippocampal volume of mice treated with lemborexant was up to 40% larger than that of untreated controls or mice given another sleep aid. Crucially, these neuroprotective effects were observed exclusively in male mice, which might indicate that the severity of tau pathology varies by sex.
Key Facts:.
Neuroprotection: Lemborexant decreased the death of brain cells and the buildup of tau in male mice.
Selective Mechanism: The benefits were only observed in sleep aids that blocked orexin receptors, such as lemborexant.
Structural Preservation: The hippocampus, a region essential to memory, had much larger volumes in treated mice.
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Researchers at Washington University School of Medicine in St. Louis have found that a common sleep aid helps mice sleep better and shields them from the brain damage associated with neurodegenerative diseases like Alzheimer’s disease. Louis.
The medication lemborexant reduces the inflammatory brain damage that tau is known to cause in Alzheimer’s disease by preventing the dangerous accumulation of an aberrant form of the protein tau in the brain.
Lemborexant and similar medications may be able to help treat or prevent tau-induced damage in a variety of neurodegenerative diseases, such as Alzheimer’s, progressive supranuclear palsy, corticobasal syndrome, and certain frontotemporal dementias, according to the study.
The research was published in Nature Neuroscience on May 27.
Senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology at WashU Medicine, stated, “We have known for a long time that sleep loss is a risk factor for Alzheimer’s disease.”.
Lemborexant has been demonstrated in this new study to enhance sleep and decrease aberrant tau, which seems to be a major contributor to the neurological damage seen in Alzheimer’s disease and a number of related conditions.
More research on this sleep aid and the creation of novel treatments that might outperform existing ones, either by themselves or in conjunction with other therapies, are anticipated as a result of this discovery.
“We currently treat patients with early, mild Alzheimer’s dementia with amyloid antibodies, which are helpful, but they don’t slow down the disease as much as we would like,” he continued.
This kind of sleep aid is worth investigating further because we need to find ways to lessen the aberrant tau buildup and the inflammation that goes along with it. We are curious as to whether targeting tau and amyloid with a combination of treatments could be more successful in reducing or halting the disease’s progression. “.”.
Holtzman and his colleagues were among the first to discover the link between proteins like tau and amyloid accumulation and inadequate sleep as a risk factor for Alzheimer’s disease.
Sleep deprivation exacerbates the amyloid and tau buildup that is characteristic of Alzheimer’s disease, according to previous research on mice genetically predisposed to this buildup. According to the most recent study, giving these mice lemborexant to improve their sleep seemed to protect them from Alzheimer’s disease by reducing the accumulation of tau protein tangles and the death of nerve cells linked to the condition.
In a number of neurological conditions, including Alzheimer’s, the protein tau builds up in the brain and results in inflammation and cell death. Lemborexant was tested by Holtzman and his team, who were co-led by first author Samira Parhizkar, PhD, a neurology instructor, in part because it affects brain regions known to be impacted by aberrant tau accumulation.
Additionally, it does not affect motor coordination, which is a problem for dementia patients using hypnotic sleep aids.
The FDA has approved three medications for sleep disorders, including lemborexant, which work as orexin receptor antagonists to block the effects of orexins, which are tiny proteins that control sleep. The two types of orexin receptors are blocked by lemborexant.
Proteins on the cell surface called receptors bind to other molecules to control cell activity. These receptors are known to be crucial for a number of physiological functions, including appetite and sleep-wake cycles.
As part of a research partnership with WashU Medicine aimed at creating novel therapies for Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative illnesses, the pharmaceutical company Eisai supplied lemborexant for these studies.
Compared to control mice, lemborexant decreased brain damage in mice genetically predisposed to damaging tau accumulation. Lemborexant recipients, for instance, displayed a 30–40% greater volume in the hippocampus, a region of the brain crucial for memory formation, than control mice and mice receiving zolpidem, a different sleep aid that comes from a different drug class.
The type of sleep aid—orexin receptor antagonist—is crucial in generating the neuroprotective effects, as Zolpidem boosted sleep but lacked the protective effects against tau accumulation in the brain observed with lemborexant.
Additionally, the researchers discovered that only male mice exhibited the positive effects, which they are still trying to figure out why.
Sustaining the structure and functionality of neurons depends on normal tau. It has a few chemical tags known as phosphate groups when it is healthy. However, tau can clump together when it absorbs too many of these chemical tags, which can cause inflammation and nerve cell death.
Lemborexant stops extra tags from being added to tau by blocking orexin receptors, the authors discovered, assisting tau in maintaining its beneficial functions in the brain.
According to Holtzman, his team is still investigating why the neuroprotective effects of lemborexant treatment were limited to male mice.
Since female mice with the same genetic predisposition to tau accumulation showed less severe neurodegeneration than male mice, he hypothesized that this could be the cause of the sex difference. Potentially helpful effects of the medication might have been less pronounced and harder to notice if there had been less damage to begin with.
Financial Support: This work was funded by the JPB Foundation, the Alzheimer’s Association (grant number AARF-21-850865), the Rainwater Foundation, the National Institutes of Health (NIH) (grant numbers P01NS074969, RF1NS090934, and RF1AG061776), and a COBRAS Feldman Fellowship.
Holtzman is the creator of a patent on the therapeutic application of anti-tau antibodies that Washington University has granted to C2N Diagnostics. Holtzman is a member of C2N Diagnostics’ scientific advisory board and co-founder.
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Closed access to the original research.
According to David M. Holtzman et al., “Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy.”. Natural Neuroscience.
abstract.
Lemborexant improves males’ neurodegeneration and tau-mediated sleep loss in a tauopathy mouse model.
Primary tauopathies and Alzheimer’s disease are two neurodegenerative diseases whose pathogenesis is linked to sleep disturbances.
In the P301S/E4 mouse model of tauopathy, we show here that the dual orexin receptor antagonist lemborexant improves tau-associated deficits in sleep-wake behavior.
By avoiding aberrant tau phosphorylation, it also shields male P301S/E4 mice from chronic reactive microgliosis and brain atrophy.
After administering the nonorexinergic medication zolpidem, which also encouraged nonrapid eye movement sleep, these neuroprotective effects in males were not seen.
In addition, lemborexant treatment and genetic ablation of orexin receptor 2 decreased wakefulness and phosphorylated tau seeding and spreading in wild-type mice’s brains.
The therapeutic potential of using orexin receptor antagonism to target sleep in order to limit tau-induced damage and stop aberrant tau phosphorylation is increased by these findings.
