Lemborexant and related sleep medicines present potential for treating tau-related problems, together with Alzheimer’s illness.
New analysis from Washington College College of Drugs in St. Louis exhibits {that a} generally used sleep remedy can restore regular sleep patterns and defend mice from the mind harm linked to neurodegenerative situations similar to Alzheimer’s illness. The drug, lemborexant, blocks the buildup of an irregular type of the tau protein within the mind, thereby lowering the irritation and mobile damage that tau sometimes causes in Alzheimer’s.
The findings point out that lemborexant, together with different medicines that act in an analogous manner, may maintain promise for treating or stopping tau-related harm in a number of neurodegenerative problems, together with Alzheimer’s illness, progressive supranuclear palsy, corticobasal syndrome, and sure types of frontotemporal dementia.
The examine was lately revealed within the journal Nature Neuroscience.
Linking sleep loss and tau buildup
“We have now identified for a very long time that sleep loss is a threat issue for Alzheimer’s illness,” mentioned senior creator David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology at WashU Drugs. “On this new examine, we now have proven that lemborexant improves sleep and reduces irregular tau, which seems to be a foremost driver of the neurological harm that we see in Alzheimer’s and several other associated problems. We’re hopeful this discovering will result in additional research of this sleep remedy and the event of latest therapeutics which may be more practical than present choices both alone or together with different obtainable remedies.
“The antibodies to amyloid that we now use to deal with sufferers with early, delicate Alzheimer’s dementia are useful, however they don’t sluggish the illness down as a lot as we want,” he added. “We want methods to scale back the irregular tau buildup and its accompanying irritation, and any such sleep support is price taking a look at additional. We’re desirous about whether or not going after each amyloid and tau with a mixture of therapies may very well be more practical at slowing or stopping the development of this illness.”
Testing lemborexant in mouse fashions
Holtzman and his colleagues had been among the many first to reveal that poor sleep is a threat issue for Alzheimer’s illness, intently linked to the buildup of proteins similar to amyloid and tau. In earlier research utilizing mice genetically predisposed to develop these protein deposits, they confirmed that sleep loss accelerates this buildup. Their latest analysis revealed that bettering sleep in these mice with lemborexant diminished tau tangles and lowered the extent of nerve cell demise sometimes related to Alzheimer’s illness.
Tau protein accumulates within the mind in a number of neurological problems, together with Alzheimer’s, the place it triggers irritation and the degeneration of neurons. Holtzman’s staff, with Samira Parhizkar, PhD, as first creator, investigated lemborexant partly as a result of it targets mind areas particularly susceptible to irregular tau buildup. Importantly, it doesn’t intrude with motor coordination, a difficulty usually raised when contemplating sleep medicines for individuals with dementia.
Mechanism of motion and comparisons
Lemborexant belongs to a category of three FDA-approved sleep medicines that act as orexin receptor antagonists. Orexins are small proteins that regulate sleep by binding to receptors on cell surfaces. By blocking each orexin receptor sorts (1 and a couple of), lemborexant disrupts orexin exercise, influencing the sleep-wake cycle and associated processes similar to urge for food regulation.
The pharmaceutical firm Eisai offered lemborexant for these research as a part of a analysis collaboration with WashU Drugs centered on growing progressive remedies for Alzheimer’s illness, Parkinson’s illness, and different neurodegenerative ailments.
In mice genetically vulnerable to dangerous tau buildup, lemborexant diminished mind harm in contrast with management mice. For instance, these receiving lemborexant confirmed 30% to 40% bigger quantity within the hippocampus — part of the mind essential for forming recollections — in contrast with management mice and people receiving a distinct sleep drug, zolpidem, which belongs to a distinct class of medicine. Zolpidem elevated sleep however had not one of the protecting results in opposition to tau accumulation within the mind that had been seen with lemborexant, suggesting that the kind of sleep support — orexin receptor antagonist — is vital in producing the neuroprotective results. The researchers additionally discovered that the helpful results had been solely seen in male mice, which they’re nonetheless working to know.
Regular tau is essential in sustaining the construction and performance of neurons. When wholesome, it carries a small variety of chemical tags known as phosphate teams. However when tau picks up too many of those chemical tags, it will possibly clump collectively, resulting in irritation and nerve cell demise. The authors discovered that by blocking orexin receptors, lemborexant prevents extra tags from being added to tau, serving to tau preserve its wholesome roles within the mind.
Holtzman mentioned his staff is constant to discover the explanations lemborexant remedy’s neuroprotective results had been seen solely in male mice. He speculated that the intercourse discrepancy may very well be as a result of remark that feminine mice with the identical genetic predisposition to tau accumulation developed less-severe neurodegeneration in contrast with male mice. With much less harm to start with, potential helpful results of the drug may have been smaller and harder to detect.
Reference: “Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse mannequin of tauopathy” by Samira Parhizkar, Xin Bao, Wei Chen, Nicholas Rensing, Yun Chen, Michal Kipnis, Sihui Track, Grace Gent, Eric Tycksen, Melissa Manis, Choonghee Lee, Javier Remolina Serrano, Megan E. Bosch, Emily Franke, Carla M. Yuede, Eric C. Landsness, Michael Wong and David M. Holtzman, 27 Might 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-01966-7
This work was supported by the Nationwide Institutes of Well being (NIH), grant numbers P01NS074969, RF1NS090934 and RF1AG061776; the JPB Basis; the Alzheimer’s Affiliation, grant quantity AARF-21-850865; the Rainwater Basis, and a COBRAS Feldman Fellowship.
Holtzman is an inventor on a patent licensed by Washington College to C2N Diagnostics on the therapeutic use of anti-tau antibodies. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics.