Microglia Depletion Restores Sleep in Alzheimer's Mouse Model

Researchers at the University of Kentucky have identified microglia, the brain's resident immune cells, as the primary drivers of sleep loss in Alzheimer's disease. In a study published in Alzheimer's & Dementia, a team led by Shannon L. Macauley, Ph.D., and first author Nicholas J. Constantino, Ph.D., demonstrated that microglial responses to amyloid plaques trigger an inflammatory cascade that disrupts sleep.

The study compared mice genetically predisposed to develop amyloid plaques with wild-type mice at six months, when plaques first emerge, and 18 months, representing late-stage disease. Using EEG monitoring and a mathematical algorithm to separate periodic and aperiodic brain activity, researchers found that sleep disruption appeared early and did not worsen despite plaque burden more than doubling by 18 months.

This ceiling effect suggests the initial immune response to early plaques causes the damage, regardless of subsequent plaque accumulation. The research also distinguished Alzheimer's pathology from normal aging: aging selectively reduces REM sleep, while amyloid pathology selectively targets non-rapid eye movement (NREM) sleep, the restorative stage critical for physical repair and toxin clearance.

To test causality, the team administered Pexidartinib (PLX3397), a drug that blocks a survival signal for microglia, for 14 days. This temporarily depleted 87% of the brain's immune cells. Mice with Alzheimer's pathology subsequently gained more than two hours of sleep per night, with longer NREM bouts and improved transitions into REM sleep.

Critically, this sleep restoration occurred without any reduction in amyloid plaque levels, indicating that the inflammatory response is a reversible cause of sleep loss independent of the plaques themselves. The findings suggest a feed-forward loop where sleep loss impairs the brain's cleaning cycle, potentially driving further damage.

The study identified specific electrical signatures distinguishing Alzheimer's from normal aging, raising the possibility of using portable EEG as an affordable, accessible biomarker for early screening in community settings. The research was funded by NIH, the Cure Alzheimer's Fund, and The CART Fund.

Macauley's lab is now investigating ways to modulate microglial activity without depleting the cells entirely. They are exploring existing medications, including the diabetes drug metformin and the anti-seizure drug stiripentol, to reset microglial metabolism and reduce overactivity. The goal is to develop non-invasive interventions that restore sleep and potentially improve quality of life years before memory loss begins.

The researchers caution that findings in mouse models require validation in humans. The study establishes a new mechanistic target but does not yet offer a clinical treatment. Future work will focus on translating the microglial modulation approach for human application.