Alzheimer’s disease affects daily rhythms, leading to symptoms such as insomnia, increased daytime napping, and confusion in the evening, known as sundowning. Researchers at Washington University School of Medicine in St. Louis have discovered that circadian rhythms in specific brain cells are altered in Alzheimer’s, impacting the regulation of numerous genes critical for brain function.
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Published in Nature Neuroscience on October 23, the study indicates that adjusting these disrupted circadian rhythms might offer new avenues for treatment. Erik S. Musiek, MD, PhD, who led the research, noted that about half of the 82 genes linked to Alzheimer’s risk are influenced by circadian rhythms. In their mouse models of the disease, the typical daily activity patterns of these genes were disrupted. Musiek emphasized the potential for developing therapies that manipulate these gene activities to slow disease progression.
Moreover, Musiek, co-director of the Center on Biological Rhythms and Sleep at WashU Medicine, pointed out that alterations in sleep patterns often arise before memory loss becomes evident, creating additional challenges for caregivers and increasing biological stress, which may accelerate the disease.
Identifying the origins of this feedback loop is critical, as the body's circadian clock regulates approximately 20% of all human genes, overseeing various biological processes. Prior research by Musiek identified a protein, YKL-40, that fluctuates in a circadian manner and is involved in regulating amyloid protein levels. Excessive YKL-40, associated with Alzheimer's risk, contributes to amyloid build-up, a characteristic of the disease.
In this new study, researchers assessed gene expression in the brains of mice with amyloid protein accumulations mimicking early Alzheimer’s stages, alongside healthy and aged mice. They collected tissue samples at two-hour intervals over 24 hours for analysis. The results indicated that amyloid disrupts the daily rhythms of hundreds of genes in microglia and astrocytes, cells important for immune response and neural communication, respectively.
While the disruption did not completely deactivate these genes, it rendered their activity less coordinated, potentially impairing essential functions like clearing amyloid from the brain. Additionally, the presence of amyloid appeared to induce abnormal rhythms in other genes that typically do not exhibit circadian patterns, particularly those linked to the brain's inflammatory response.
Musiek concluded that these findings support further exploration into therapies aimed at targeting the circadian cycles of microglia and astrocytes, which could be key to maintaining healthy brain functions and possibly preventing the progression of Alzheimer's disease.