Alzheimer’s disease may progress by disrupting the brain’s biological clock, which affects gene activity in cells responsible for clearing amyloid plaques and maintaining brain health. Researchers at Washington University School of Medicine in St. Louis have found that this disruption impairs the circadian rhythms within specific brain cells, changing the timing and activity of numerous genes essential for brain functions. Their study, published in Nature Neuroscience, suggests that restoring these internal rhythms might represent a novel therapeutic approach to combat Alzheimer’s.
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Erik S. Musiek, MD, PhD, who led the study, noted that 82 genes are associated with Alzheimer’s disease risk, and approximately half of these are regulated by the circadian rhythm. In mouse models designed to mimic Alzheimer’s, researchers observed that the normal daily patterns of these genes were disturbed, indicating a potential pathway for developing treatments targeting these regulations to slow disease progression.
Sleep disturbances are commonly reported by caregivers of individuals with Alzheimer’s, often presenting years before noticeable memory loss. Disruptions in sleep not only add to the challenges faced by patients and caregivers but can also trigger biological stress that exacerbates disease progression. Understanding the source of these disruptions is crucial, as the circadian clock affects about 20% of all human genes, influencing processes such as digestion and immune responses.
Musiek previously identified a protein called YKL-40 that fluctuates with the circadian cycle and helps regulate amyloid levels in the brain. Elevated levels of YKL-40 are linked to an increased risk of Alzheimer's, leading to amyloid accumulation, which is a hallmark of the disease.
In their new research, the team found that amyloid disrupts daily rhythms of hundreds of genes in critical brain cells, including microglia and astrocytes. Microglia act as the brain's immune defenders by clearing toxins, while astrocytes support neuron communication. The affected genes are crucial for microglia in breaking down waste, including amyloid.
While gene activity was not entirely halted, the synchronization of their timing was lost, diminishing the brain's capacity to clear amyloid effectively. Furthermore, amyloid initiated new rhythmic patterns in genes that typically do not follow a circadian schedule, many of which are involved in inflammation and the brain's response to stress.
The study indicates that treatments aimed at adjusting circadian rhythms in microglia and astrocytes could help maintain healthy brain function. Musiek emphasized the need to manipulate the circadian clock to either strengthen or weaken its influence in certain cell types, with the ultimate goal of optimizing the circadian system to prevent amyloid buildup and mitigate Alzheimer’s disease symptoms.
The research was supported by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.