Scientists at the University of Kentucky have identified an unexpected mechanism behind sleep disruption in Alzheimer’s disease: overactive immune cells in the brain, rather than amyloid plaques themselves.
In a study published in Alzheimer’s & Dementia, researchers led by Shannon L. Macauley found that temporarily eliminating approximately 87% of microglia—specialized immune cells in the brain—restored more than two hours of sleep per day in mice with Alzheimer’s-like pathology. This occurred without removing the amyloid plaques characteristic of the disease.
Microglia normally protect the nervous system by removing debris and responding to injuries. However, when these cells detect amyloid plaques, their response can become excessive. Rather than simply addressing the threat, they release inflammatory signals that interfere with normal brain function and sleep cycles.
“Microglia are immune cells that, when they respond to plaques, kick off this elaborate cascade of inflammation, as if the microglia are partying all night, and keeping the brain awake,” according to Macauley. The team compared this widespread inflammatory response to a defensive mechanism that causes more disruption than the original problem.
To conduct the study, researchers examined two groups of mice at different ages: six months (when plaques first appeared) and 18 months (with more advanced pathology). They used electroencephalography (EEG) and electromyography (EMG) to measure sleep patterns and identify different sleep stages. Light-sheet microscopy allowed them to visualize the distribution of plaques and microglia across the brain.
The team administered Pexidartinib (PLX3397), a drug originally developed for cancer research that blocks a cellular signal microglia depend on for survival. After 14 days of treatment, microglia were largely depleted, allowing researchers to test whether sleep would improve.
A surprising finding emerged: sleep problems did not progressively worsen as amyloid plaques accumulated. Researchers initially expected increasing plaque buildup to cause progressively worse sleep disturbances. Instead, the mice developed substantial sleep problems early in the disease process, with those problems remaining largely unchanged despite plaque levels more than doubling by 18 months. The researchers described this pattern as a ceiling effect.
These findings suggest a potential new approach to treating one of Alzheimer’s most disruptive symptoms by targeting the immune response rather than focusing solely on plaque removal.
Key facts
- Researchers restored over 2 hours of daily sleep in Alzheimer’s mice by temporarily removing 87% of brain microglia immune cells
- Sleep improvement occurred without removing amyloid plaques, suggesting inflammation—not plaques alone—drives sleep disruption
- Microglia’s inflammatory response to plaques may cause more brain disruption than the plaques themselves
- Sleep problems emerged early in disease progression and did not worsen despite plaque levels more than doubling over 12 months
- Study was published in Alzheimer’s & Dementia and led by University of Kentucky researchers Shannon L. Macauley and Nicholas J. Constantino