Alzheimer’s disease often leads to disruptions in a person’s usual circadian rhythm. Insomnia, restless sleep and frequent daytime naps are typical early manifestations of the disease. In later stages, patients often experience the so-called “sunset syndrome,” a period of disorientation and increased arousal that usually occurs in the evening. These symptoms indicate a close connection between the development of Alzheimer’s disease and the circadian system, an internal biological mechanism that regulates sleep, wake cycles and other circadian processes.
Scientists at Washington University School of Medicine in St. Louis have shown in a mouse model that Alzheimer’s disease disrupts circadian rhythms in certain types of brain cells. These disruptions alter the activity of hundreds of genes, affecting the timing and intensity of their switching on and off, resulting in disruptions in key processes necessary for normal brain function. The results of the study, published in the journal Nature Neuroscience, indicate that restoring or maintaining the stability of internal biorhythms could be a new direction in the treatment of Alzheimer’s disease.
Because the symptoms of Alzheimer’s disease often repeat from day to day, researchers hypothesized that genes and proteins that follow circadian rhythms may be involved. In a new experiment, they analyzed gene activity in the brains of three groups of mice: those with amyloid accumulation, healthy young mice, and older animals without amyloid plaques. Tissue samples were collected every two hours throughout the day, which made it possible to track how gene expression changes depending on the time of day. The results showed that amyloid deposits disrupt the normal rhythmic activity of hundreds of genes in two key types of brain cells – microglia and astrocytes. Microglia play the role of the brain’s immune system, clearing it of toxins and cellular waste, while astrocytes provide communication between neurons and maintain the stability of their functioning. Many of the genes whose activity was disrupted are typically responsible for microglia’s ability to remove waste, including amyloid itself. Although these genes did not stop working completely, their normal coherence and rhythm were disrupted, causing the brain’s detoxification system to become less effective.
The scientists also found that amyloid plaques likely create new rhythmic cycles in gene activity that are not typically associated with diurnal fluctuations. Most of these genes are involved in inflammatory processes and stress responses in the brain that occur when its internal balance is disrupted.