Researchers at the University of Kentucky report that overactive microglia—immune cells in the brain—can drive sleep loss in mice with amyloid plaques. In the study, temporarily depleting most microglia restored more than two hours of sleep per day, even though plaque levels did not change.
Researchers at the University of Kentucky say they have identified an immune-driven mechanism that disrupts sleep in a mouse model of Alzheimer’s disease—and shown that the sleep loss can be reversed without reducing amyloid plaques.
In a study published in Alzheimer’s & Dementia, the team—led by Shannon L. Macauley, PhD, an associate professor of physiology, and first author Nicholas J. Constantino, PhD—found that microglia, the brain’s resident immune cells, were the main drivers of sleep loss in mice genetically prone to develop amyloid plaques.
Macauley described the microglial response to plaques as a disproportionately large reaction to a localized problem, likening it to a “whole house response.” She said the resulting inflammatory cascade can keep the brain awake. Constantino reported that sleep disruption appeared early—when plaques first emerged—and did not worsen by 18 months of age, even though plaque burden more than doubled.
To test whether microglia were causing the sleep disruption, the researchers used pexidartinib (also referred to as PLX3397) for 14 days to temporarily eliminate most microglia. After treatment, about 87% of the cells were depleted, and mice with Alzheimer’s-related pathology regained more than two hours of sleep per day, including longer periods of non-rapid eye movement (NREM) sleep. The team reported that the improvement occurred even though amyloid plaque levels remained unchanged.
The study also distinguished effects linked to aging from those tied to amyloid pathology. The researchers reported that normal aging primarily reduced rapid eye movement (REM) sleep, while amyloid pathology selectively reduced NREM sleep, the deep, restorative stage.
Looking ahead, the laboratory plans to examine whether existing medicines can reduce microglial overactivity without eliminating the cells. The researchers said they are studying drugs already in use—including the diabetes medication metformin and the antiseizure drug stiripentol—as potential ways to alter microglial energy use and dampen inflammatory activity.
