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Scientists at the University of Kentucky have restored more than two hours of sleep in an animal model of Alzheimer’s disease by temporarily eliminating microglia, the brain’s resident immune cells, according to a study published in the journal Alzheimer’s & Dementia. Led by Shannon L. Macauley, an associate professor of physiology in the UK College of Medicine, and recent doctoral graduate Nicholas J. Constantino, the research shifts the prevailing scientific understanding of sleep disruption in neurodegenerative disorders away from dying neurons and physical plaque accumulation toward broad immune system activation.
The Mechanism of Alzheimer’s Sleep Loss
For years, researchers attributed sleep disturbances in Alzheimer’s patients primarily to the physical buildup of amyloid-beta plaques or the progressive loss of damaged neurons. However, the University of Kentucky team identified a broader inflammatory cascade as the primary driver. According to Macauley, amyloid plaques act like a small fire in a kitchen, while microglia function like an automatic sprinkler system that ends up flooding the house. Rather than simply cleaning up cellular debris, these immune cells trigger a continuous inflammatory response that keeps the brain in an active state.
“Basically, we showed that it is not the plaques themselves, or solely dysfunctional neurons, that cause sleep loss but actually microglia,” Macauley stated according to university reporting. She described the hyperactive immune cells as “partying all night” and disrupting normal brain rhythms.
Tracking Brain Activity and Immune Cells
To separate the effects of Alzheimer’s disease from normal aging, researchers examined two groups of mice: subjects with a genetic predisposition to develop amyloid-beta plaques and wild-type control mice that aged normally. Evaluations occurred at six months of age, when plaques initially emerge, and at 18 months of age, representing advanced disease stages.
The research team utilized head-mounted devices to record electroencephalography (EEG) and electromyography (EMG). The EEG captured electrical fingerprints and network oscillations, while the EMG tracked muscle movement, allowing scientists to differentiate between waking states, deep restorative sleep, and rapid eye movement (REM) sleep. To map the spatial distribution of the immune cells, the team used light-sheet microscopy, a technique that renders brain tissue transparent and applies a laser plane to generate a high-resolution 3D digital map of both plaques and microglia throughout the brain.
Restoring Sleep Through Microglial Depletion
To test whether microglia directly caused the sleep deficits, the scientists administered a drug called Pexidartinib (PLX3397). Originally developed for cancer research, the medication inhibits a signaling pathway essential for microglial survival. Administering the drug to the mice for 14 days temporarily eliminated approximately 87% of the brain’s immune cells.
Following this depletion, the animals regained more than two hours of sleep each day. To analyze the underlying electrical changes, the team applied a mathematical algorithm known as Fitting Oscillations and One Over Frequency to separate periodic rhythmic brain waves from aperiodic background electrical noise.
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