Imagine a small fire starting in a corner of your kitchen. With the right fire extinguisher, you may be able to extinguish the fire quickly. Instead, the sprinkler system kicks in and floods your entire home, turning a contained problem into widespread damage.
Researchers say something similar may occur in the brains of Alzheimer’s patients. Amyloid plaques, sticky protein clumps that accumulate in the brain, are like fire. Microglia, the brain’s resident immune cells, function like sprinklers. Although their reactions are intended to protect the brain, they can ultimately make the situation worse.
Now, a team from the University of Kentucky has identified this harmful process for the first time and demonstrated how to stop it.
Brain immune cells linked to sleep deprivation in Alzheimer’s disease
In a study published in a journal Alzheimer’s disease and dementiaResearchers led by Dr. Shannon L. McCauley, Associate Professor of Physiology at the UK Medical School, and lead author Dr. Nicholas J. Constantino, a recent UK PhD graduate, found that microglia are the main cause of sleep deprivation in animal models of Alzheimer’s disease.
When the researchers used a drug to temporarily eliminate most of these cells, the animals regained more than two hours of sleep each day. The results represent a potential new therapeutic target for the disease, which McCauley called a “paradigm shift.”
Scientists previously thought that sleep deprivation associated with Alzheimer’s disease was primarily caused by neuronal damage or the physical presence of amyloid plaques. The new findings suggest that this disruption may stem from a broader immune response, similar to a “whole-house response.”
“Essentially, we showed that it’s not the plaques themselves or simply malfunctioning neurons that cause sleep deprivation, but actually microglia,” McCauley said. “Microglia are immune cells, and when they react to plaque, they start this elaborate inflammatory cascade, as if they were partying all night to keep the brain awake.”
Sleep and brain activity tracking
To distinguish between changes associated with Alzheimer’s disease and those caused by normal aging, researchers studied two groups of mice. One group had a genetic predisposition to developing amyloid plaques, and the other group consisted of “wild-type” mice that aged normally.
Animals were examined at 6 months of age, when plaques began to appear, and again at 18 months, a stage indicative of advanced disease.
The team used several advanced tools to carefully monitor changes in sleep and brain activity. The mice were fitted with a small head-mounted device that recorded electroencephalography (EEG) and electromyography (EMG).
EEG captures patterns of electrical activity and vibrations across brain networks, creating what is considered an electrical fingerprint of the brain. EMG measures muscle activity. By combining the two methods, researchers were able to accurately determine when animals were awake and in deep restorative sleep or dreaming sleep.
To find immune cells that, as McCauley described, were “partying all night”, the researchers also used a technique called light-sheet microscopy. The method involves making brain tissue transparent and using a thin plane of laser light to build detailed 3D digital images.
This approach gave the team a complete picture of both amyloid plaques and immune cells throughout the brain.
Temporary removal of microglia
To find out whether microglia actually cause sleep problems, scientists used a drug called pexidartinib (PLX3397). The drug was first developed for cancer research and blocks signaling pathways that microglia rely on for survival.
When mice were given the drug for 14 days, about 87% of their brain’s immune cells were temporarily eliminated. Researchers were now able to determine whether people slept better in their absence.
The researchers also used a mathematical technique called fitting oscillations and one-over frequency to separate the brain’s electrical activity into two categories: periodic activity (rhythmic waves that we normally think of as brain waves) and aperiodic activity (background electrical noise).
Using the car comparison, the researchers were effectively testing whether the brain’s engine continues to run at abnormally high speeds even when the animals are at rest.
Early plaque causes permanent sleep deprivation
Mr McCauley called the results “surprising and unexpected”. The results showed that while plaque buildup and sleep disturbances steadily decreased, they did not simultaneously worsen.
“We expected that as the plaque burden became more severe, the sleep problems would also worsen,” Constantino said. “Disturbances in sleep and cortical brain wave activity that occur at six months, when plaques first appear, did not worsen after 18 months, even though the amount of plaques had more than doubled.”
The research team described this pattern as a ceiling effect. Even though plaque levels more than doubled, the amount of sleep lost remained about the same.
This result suggests that the first wave of immune activity triggered by early plaques may be sufficient to establish sleep problems. Additional plaque does not result in a proportional increase in sleep problems.
Alzheimer’s disease targets restorative sleep
This study also helped distinguish between the effects of normal aging and those associated with Alzheimer’s disease.
Normal aging primarily reduces rapid eye movement (REM) sleep, a stage associated with dreams and memory consolidation. In contrast, amyloid pathology selectively reduces non-rapid eye movement (NREM) sleep, a deep restorative phase of sleep.
“Restorative sleep is critical for the body’s repair, learning, memory, and flushing out the day’s toxins,” McCauley says. “When Alzheimer’s patients lose this stage, the brain’s primary cleansing cycle is lost, creating a feedforward loop that can cause further damage.”
Therefore, if this recovery period is lost, a harmful cycle can occur. Lack of sleep can reduce the brain’s ability to remove waste products, which can lead to further damage and further sleep disruption.
Recovered more than 2 hours of sleep
The most surprising results were obtained after the researchers depleted microglia.
Mice with Alzheimer’s disease-related conditions were able to get more than two hours of sleep each night after most of their brain’s immune cells were removed. Periods of restorative non-REM sleep are also longer, giving you more opportunities to enter healthy dream sleep that supports the formation of new memories.
Importantly, the improvement was seen even though the amount of amyloid plaques in the brain remained unchanged.
This finding suggests that the inflammatory response to plaque may be a reversible cause of sleep deprivation and may be treated separately from the plaque itself.
This also raises big questions for future research. Could restoring this essential sleep in people help interrupt the feedforward loop associated with Alzheimer’s disease?
Collaborative lab culture
This discovery emerged from the research environment of the McCauley lab in the Physiology Department at the Sanders-Brown Center on Aging. Ms McCauley said the progress was due to a “beautiful partnership” between herself, her students and other trainees.
“I love people who take initiative, are curious about their passions, and keep striving to find answers,” McCauley said.
She encourages her team members to be “calculated risk takers” and has a quote from Wayne Gretzky in her office: “You’ll miss 100 percent of the shots you don’t take.”
Constantino, who recently defended his PhD in the UK, said the atmosphere gave him the confidence to pursue difficult problems across multiple disciplines.
“Dr. McCauley also taught me to embrace uncertainty and failure as part of the scientific process,” Constantino said. “Some of the most interesting studies I’ve been a part of turned out to be because our initial hypothesis was wrong.”
When an experiment hits a snag, McCauley encourages his team to continue investigating rather than stopping.
“Track your data and ask better questions to understand what’s really going on.”
This approach helped researchers move beyond the field’s traditional focus on neurons and investigate whether microglia could be a therapeutic target.
Portable EEG may help in early detection
The broader goal of the research is to develop affordable, non-invasive tools for people living with Alzheimer’s disease. The current findings provide several directions for future research.
Researchers have identified patterns of electrical activity in the brain that appear to distinguish changes associated with Alzheimer’s disease from normal aging. They believe that EEG technology could eventually serve as a “readily accessible, affordable, long-term biomarker for Alzheimer’s disease.”
“Portable EEG systems have the potential to monitor people in their home environment and screen for changes associated with Alzheimer’s disease without first requiring expensive or invasive tests,” McCauley said.
Such equipment could allow local clinics across Kentucky to screen at-risk people before they travel long distances to larger hospitals for more specialized tests.
Calming microglia without eliminating them
McCauley’s lab is currently investigating ways to reduce microglial overactivity without eliminating the cells entirely.
The research team is investigating safe drugs already in use, including the diabetes drug metformin and the anti-epileptic drug Stiripentol. The researchers want to see if these drugs can change the way microglia process energy and reduce their tendency to become overactive.
By preventing immune cells from keeping the brain’s engines running high, the researchers hope to restore healthy sleep and improve quality of life years before significant memory loss occurs.
“If we can target that process, we may be able to improve quality of life, attention, cognition, and confusion,” McCauley said.
Finding an effective solution begins with identifying both the cause of the problem and the appropriate tools to address it. McCauley’s team is making progress on both fronts.
Research reported in this publication 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 Medicine of the National Institutes of Health under award numbers P30GM127211 and P20GM148326. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This research was supported by a $287,236 award from the Alzheimer’s Disease Treatment Fund.
This research was supported by a $250,000 award from the CART Fund (Coin for Alzheimer’s Disease Research Trust).
