Brain immune cells appear to drive reversible sleep loss in mice with Alzheimer’s-like disease.
A fire starts in one room, but instead of containing the danger, the sprinkler system floods the entire house. The response causes far more damage than the original threat.
Something similar may happen in Alzheimer’s disease. Amyloid plaques, the sticky protein deposits that accumulate in the brain, resemble the small fire. Microglia, the brain’s immune cells, act like the sprinklers. Their attempt to respond to the plaques may end up disrupting the wider brain.
University of Kentucky researchers have now identified this process in mice and shown that it can be interrupted.
In a study published in Alzheimer’s & Dementia, researchers led by Shannon L. Macauley, Ph.D., an associate professor of physiology in the UK College of Medicine, and first author Nicholas J. Constantino, Ph.D., a recent UK doctoral graduate, found that microglia were the main drivers of sleep loss in the animal models. Temporarily eliminating most of these cells with a drug restored more than two hours of sleep each day, revealing a possible treatment target that Macauley called “paradigm shifting.”
Microglia drive sleep loss in mice
Sleep disruption in Alzheimer’s was previously attributed largely to dying neurons or the physical presence of amyloid plaques. The findings instead point to a broader inflammatory response involving the brain’s immune system.
“Basically, we showed that it is not the plaques themselves, or solely dysfunctional neurons, that cause sleep loss but actually microglia,” said Macauley. “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.”
To separate disease-related effects from ordinary aging, the researchers compared mice genetically predisposed to develop amyloid plaques with “wild-type” mice that aged normally. They examined both groups at six months, when plaques first appeared, and again at 18 months, representing more advanced disease.
Tiny head-mounted devices recorded electroencephalography (EEG) and electromyography (EMG). EEG captures characteristic patterns of electrical activity across the brain, while EMG records muscle movement. Together, these measurements showed precisely when each mouse was awake, in deep restorative sleep, or in dreaming sleep.
The researchers also used light-sheet microscopy to locate the immune activity Macauley described as “partying all night.” The method makes brain tissue transparent, then scans it with a narrow sheet of laser light to produce a detailed 3D map. This gave the researchers a view of plaques and immune cells across the entire brain.
To test whether microglia were directly responsible for the disrupted sleep, the mice received Pexidartinib (PLX3397), a medication first developed for cancer research. The drug blocks a survival signal required by microglia. After 14 days of treatment, about 87% of the brain’s immune cells had been temporarily removed, allowing the researchers to determine whether sleep returned.
They also analyzed the EEG recordings with an algorithm called Fitting Oscillations and One Over Frequency (FOOOF). It separated periodic activity, the familiar rhythmic patterns called brain waves, from aperiodic activity, the background electrical noise of the brain.
In automotive terms, the analysis tested whether the brain’s engine remained unusually active even while the animal was resting.
Sleep loss plateaus as plaques multiply
Macauley described the findings as “mind-blowing and unexpected.” Rather than steadily worsening as plaques accumulated, sleep disruption reached a limit early in the disease.
“I expected that as plaque burden became more severe, sleep disruption would also worsen,” said Constantino. “The disruptions in sleep and cortical EEG activity that occur at 6 months, when plaques first emerge, did not worsen by 18 months, despite more than double the amount of plaque burden.”
The researchers called this a ceiling effect. Although plaque levels more than doubled, the loss of sleep did not intensify. The pattern suggests that the initial inflammatory response to early plaques may trigger the disruption, while additional plaques do not necessarily increase it further.
The study also distinguished the effects of normal aging from those associated with amyloid pathology. Aging primarily reduced rapid eye movement (REM) sleep, the phase linked to dreaming and memory consolidation. Alzheimer’s related pathology instead selectively disrupted non-rapid eye movement (NREM) sleep.
NREM is the main restorative stage of sleep. “That restorative sleep is super important for physical repair, learning and memory and washing out the toxins of the day,” Macauley said. When Alzheimer’s patients lose this stage, they lose their brain’s primary cleaning cycle, creating a feed-forward loop that may drive further damage.”
Removing microglia restores lost sleep
The clearest evidence came after the researchers depleted the microglia. Mice with Alzheimer’s related pathology slept more than two additional hours each night. Their periods of restorative NREM sleep also became longer, increasing their opportunities to enter dreaming sleep that supports the formation of new memories.
The improvement occurred without reducing the amount of amyloid plaque in the brain. That result indicates that the inflammatory response, rather than plaque burden alone, may be a reversible source of sleep disruption that can be addressed independently.
The finding also raises a central question for future research: whether restoring this sleep in people could interrupt the self-reinforcing cycle between poor sleep and further brain damage.
Unexpected results redirect the research
The work emerged from the research culture within Macauley’s laboratory in the Department of Physiology at the Sanders-Brown Center on Aging. Macauley attributed the discovery to a “beautiful partnership” with the laboratory’s students and trainees.
“I love people who take initiative, find their passion, are curious and keep pushing to find an answer,” Macauley said. She encourages her team to be “calculated risk-takers,” and keeps a quote in her office by Wayne Gretzky: “You miss 100% of the shots you don’t take.”
Constantino, who recently defended his doctorate at UK, said this environment gave him the freedom to pursue questions spanning several fields. “Dr. Macauley has also taught me to embrace uncertainty and failure as part of the scientific process,” Constantino said. “Some of the most interesting studies I have been a part of emerged because our original hypothesis was wrong.” Instead of stopping at an obstacle, Macauley tells her team: “Follow the data, ask better questions, and figure out what is actually happening.”
That approach encouraged the researchers to investigate microglia instead of remaining within the field’s traditional focus on neurons.
Portable EEG could expand early screening
The broader aim is to develop affordable and noninvasive tools for people facing Alzheimer’s disease. The current findings provide several directions that future studies can pursue.
The researchers identified electrical brain patterns that differentiated Alzheimer’s related pathology from normal aging. They propose that EEG could become a “readily accessible, affordable and longitudinal biomarker of Alzheimer’s disease.”
“Portable EEG systems could allow us to monitor people in their home environments and potentially screen for changes associated with Alzheimer’s disease, without the initial need for expensive or invasive tests,” Macauley said. Local clinics across Kentucky could potentially use such systems to evaluate people at risk before sending them on lengthy trips for specialized testing at major hospitals.
Macauley’s laboratory is also studying ways to reduce microglial overactivity without eliminating the cells. The researchers are evaluating existing medications, including the diabetes drug Metformin and the anti-seizure drug Stiripentol, to alter how microglia process fuel and limit their inflammatory activity. Their goal is to quiet the immune response, restore sleep, and improve quality of life before memory loss becomes apparent.
“If we can target that process, it might help with quality of life, attention, cognition and confusion,” Macauley said.
By identifying both a likely cause of the sleep disruption and a way to intervene, the researchers have established a foundation for future treatment and screening studies.
Reference: “Early microglial response to amyloid plaques drives sleep loss in Alzheimer’s disease” by Nicholas J. Constantino, Riley E. Irmen, Matthew J. Lanning, Sierra M. Turner, Clair C. Ashley, Caitlin M. Carroll, Evan M. Neary, Dave Rubinow, J. Andy Snipes and Shannon L. Macauley, 7 June 2026, Alzheimer’s & Dementia.
DOI: 10.1002/alz.71579
This work was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG068330, R01AG093847 and P30AG072946, and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers P30GM127211 and P20GM148326.
This work was supported by a $287,236 award from the Cure Alzheimer’s Fund.
This work was supported by a $250,000 award from The CART Fund (Coins for Alzheimer’s Research Trust).
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.