Pexidartinib Hydrochloride

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Scientists have uncovered an unexpected culprit behind sleep loss in Alzheimer’s disease: overactive immune cells in the brain. By temporarily removing these cells, researchers restored more than two hours of sleep per day in mice, revealing a promising new target for treatment.Scientists have discovered an unexpected reason why Alzheimer's disease disrupts sleep, and their findings suggest that the problem may be reversible. In experiments involving mice with Alzheimer's-like brain changes, researchers restored more than two hours of sleep per day without removing the amyloid plaques associated with the disease. The surprising discovery points to an overlooked culprit: the brain's own immune cells. Rather than simply protecting the brain from damage, these cells can trigger inflammation that interferes with healthy sleep. Researchers at the University of Kentucky found that temporarily eliminating most of these immune cells allowed the mice to sleep longer and spend more time in the deep, restorative stages of sleep. The results suggest a potential new approach to treating one of the most disruptive symptoms of Alzheimer's disease. The findings, published in the journal Alzheimer's & Dementia, were reported by a team led by Shannon L. Macauley, Ph.D., an associate professor of physiology at the University of Kentucky College of Medicine, and first author Nicholas J. Constantino, Ph.D., a recent doctoral graduate. Macauley described the discovery as "paradigm-shifting" because it challenges the prevailing understanding of why people with Alzheimer's often experience severe sleep problems. How the Brain's Immune System Can Disrupt Sleep To understand what the researchers uncovered, imagine a small fire breaking out in a kitchen. Instead of containing the flames, the building's sprinkler system activates everywhere, flooding the entire house and causing widespread damage. Something similar may happen in the brain during Alzheimer's disease. Amyloid plaques are deposits of sticky protein fragments that accumulate between nerve cells. They are one of the characteristic features of Alzheimer's and have long been investigated for their role in the disease. The brain also contains specialized immune cells known as microglia. These cells normally protect the nervous system by removing debris, responding to injuries, and helping maintain a healthy environment for neurons. However, when microglia detect amyloid plaques, their defensive response can become excessive. Instead of simply addressing the threat, they release inflammatory signals that may interfere with normal brain activity. Scientists have traditionally linked sleep problems in Alzheimer's primarily to damaged neurons or the accumulation of amyloid plaques. The new findings suggest that the immune system's reaction to those plaques plays a major role. "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." In other words, the brain's response to Alzheimer's pathology may create additional problems beyond those caused by the plaques themselves. The researchers compared this widespread reaction to a "whole house response," in which a defense mechanism ends up causing more disruption than expected. Tracking Alzheimer's Sleep Changes Inside the Brain To investigate the connection between microglia and sleep, the scientists studied two groups of mice. One group was genetically predisposed to develop amyloid plaques, while the other consisted of normal "wild-type" mice that experienced typical aging. The researchers examined the animals at two ages: six months, when plaques first appeared in the genetically modified mice, and 18 months, when the disease model showed more advanced pathology. Comparing these groups helped the scientists distinguish changes associated with Alzheimer's pathology from those that naturally occur as the brain ages. The team used several advanced technologies to measure sleep and examine what was happening inside the brain. Each mouse was fitted with a small device that recorded electroencephalography (EEG) and electromyography (EMG). EEG measures the brain's electrical activity, including the patterns and rhythms produced when networks of neurons communicate. These electrical signals change depending on whether the brain is awake, dreaming or experiencing deep sleep. EMG measures electrical activity in muscles. Combining the two techniques allowed researchers to identify different sleep stages and determine how long the animals remained in each one. The scientists also wanted to visualize the relationship between amyloid plaques and immune cells throughout the brain. For this, they used light-sheet microscopy, an imaging technique that makes biological tissue transparent and illuminates it with a thin layer of laser light. The resulting images can be assembled into detailed three-dimensional maps, allowing scientists to examine structures that would otherwise be difficult to see. This approach revealed the distribution of plaques and microglia across the brain, helping researchers understand where immune cells were responding to Alzheimer's pathology. Scientists Temporarily Remove 87% of Brain Immune Cells To determine whether microglia were actually responsible for disrupted sleep, the team conducted an experiment designed to temporarily eliminate most of these cells. The researchers administered a drug called Pexidartinib (PLX3397), which was originally developed for cancer research. It blocks a cellular signal that microglia depend on for survival. After the mice received the medication in their food for 14 days, approximately 87% of their microglia had been depleted. This allowed the scientists to test whether sleep would improve when the cells driving the inflammatory response were largely absent. The researchers also performed a detailed analysis of the animals' brain activity using a mathematical method called Fitting Oscillations and One Over Frequency (FOOOF). This technique separates electrical signals into periodic activity (the rhythmic waves we usually think of as brain waves) and aperiodic activity (the background electrical noise). By examining these different components, the team could identify changes in how the brain was functioning, including whether it remained unusually active during periods when it should have been resting. The process is somewhat like monitoring a car engine to determine whether it continues running at high speed even when the vehicle is supposed to be idle. A Surprising Discovery About Alzheimer's Brain Plaques Macauley called the results "mind-blowing and unexpected." One of the most surprising findings was that sleep problems did not continue worsening as amyloid plaques accumulated. The researchers initially expected that increasing plaque buildup would lead to progressively more severe sleep disturbances. Instead, the mice developed substantial sleep problems relatively early, and those problems remained largely unchanged even as plaque levels increased dramatically. "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 team described this pattern as a ceiling effect. Essentially, sleep disruption appeared to reach a certain level early in the disease process rather than increasing in direct proportion to the amount of amyloid in the brain. This suggests that the initial inflammatory response triggered by plaques may be particularly important. Once microglia become activated and disrupt sleep, additional plaque accumulation may not necessarily produce an equivalent increase in sleep loss. The discovery offers an important clue as to why sleep disturbances can emerge relatively early in Alzheimer's disease. Alzheimer's Disrupts a Different Type of Sleep Than Normal Aging The study also revealed a notable difference between sleep changes caused by normal aging and those associated with Alzheimer's pathology. Sleep is not a single, uniform state. Throughout the night, the brain moves through several stages that perform different functions. Rapid eye movement (REM) sleep is strongly associated with vivid dreaming and plays an important role in processing memories. The researchers found that normal aging primarily reduced this type of sleep. Alzheimer's pathology, however, had a different effect. It selectively disrupted non-rapid eye movement (NREM) sleep, which includes the deepest and most physically restorative stages of sleep. During NREM sleep, the brain performs essential maintenance functions that support learning, memory, and recovery. Deep sleep is also associated with processes that help clear metabolic waste products from the brain. "That restorative sleep is super important for physical repair, learning and memory and washing out the toxins of the day," Macauley said. Losing this important stage of sleep could have consequences beyond daytime fatigue. Because healthy sleep helps maintain the brain's internal environment, disruptions may interfere with processes that normally remove potentially harmful waste. Researchers suspect this could contribute to a self-reinforcing cycle in which Alzheimer's pathology disturbs sleep, and inadequate sleep may further aggravate the disease. Breaking that cycle could therefore become an important treatment strategy. More Than Two Hours of Sleep Restored Without Removing Plaques The most striking result emerged after the researchers temporarily removed most of the microglia from the brains of mice with Alzheimer's-like pathology. The animals gained more than two hours of sleep per day. They also experienced longer periods of restorative NREM sleep, giving them more opportunities to transition naturally into REM sleep, which is important for memory formation. Even more surprisingly, these improvements occurred without any reduction in amyloid plaque levels. The plaques were still present, but the mice were sleeping substantially better. This finding provides evidence that the inflammatory response driven by microglia contributes directly to sleep disruption and that suppressing this response can reverse at least some of the associated sleep problems. It also suggests that researchers may not need to eliminate amyloid plaques to improve sleep in Alzheimer's disease. Although these findings are promising, the experiments were conducted in mice, and the same benefits have not yet been demonstrated in people. Temporarily removing most of the brain's immune cells is also not an established or practical treatment for Alzheimer's patients. The researchers are now interested in whether the beneficial effects can be reproduced by adjusting microglial activity rather than eliminating the cells themselves. If such an approach eventually proves successful in humans, it could provide a way to improve sleep and potentially reduce some of the additional stress that poor sleep places on the brain. The Research Team Behind the Discovery The work was conducted in Macauley's laboratory in the Department of Physiology at the University of Kentucky's Sanders-Brown Center on Aging. Macauley credits the achievement to a "beautiful partnership" with students and researchers who were willing to challenge established ideas about Alzheimer's disease. "I love people who take initiative, find their passion, are curious, and keep pushing to find an answer," Macauley said. She encourages members of her laboratory to be "calculated risk-takers," emphasizing that meaningful discoveries often require scientists to investigate possibilities that may initially seem unlikely. A quote from hockey legend Wayne Gretzky hangs in her office: "You miss 100% of the shots you don't take." Constantino, who recently completed his doctorate at the university, said the laboratory's collaborative environment encouraged him to pursue questions that crossed traditional scientific disciplines. "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." Macauley reinforces this mindset with a simple instruction to her team: "Follow the data, ask better questions, and figure out what is actually happening." That approach helped the researchers move beyond the traditional emphasis on neurons and amyloid plaques to examine the broader role of the brain's immune system. Could Existing Medications Help Restore Sleep in Alzheimer's? The research team is now exploring ways to translate these findings into treatments and diagnostic tools that could eventually benefit people with Alzheimer's disease. One promising direction involves calming overactive microglia without removing them. Because microglia perform essential protective functions, eliminating them is not an ideal long-term strategy. Instead, the researchers hope to modify how these immune cells respond to amyloid plaques and regulate inflammation. The laboratory is investigating existing medications, including the diabetes drug Metformin and the anti-seizure medication Stiripentol. These drugs are being studied for their potential to alter how microglia produce and use energy, a process known as cellular metabolism. Changing that energy use could potentially reduce excessive immune activation and its harmful effects on sleep. The hope is to prevent the brain's inflammatory response from becoming so intense that it disrupts normal sleep activity. Researchers are particularly interested in whether intervention during the earlier stages of Alzheimer's could improve sleep and quality of life before substantial memory loss develops. "If we can target that process, it might help with quality of life, attention, cognition and confusion," Macauley said. The proposed drug strategies remain experimental for this purpose, and additional research will be necessary to determine whether they can safely produce similar benefits in humans. A Simpler Way to Detect Early Alzheimer's Changes Beyond identifying a potential treatment target, the study uncovered electrical activity patterns that may help distinguish Alzheimer's pathology from normal brain aging. The researchers believe these patterns could eventually make EEG a useful tool for detecting and monitoring changes associated with Alzheimer's disease. Unlike more expensive imaging procedures, EEG records electrical signals through electrodes placed on the scalp. It is relatively affordable, does not require surgery, and can be repeated to follow changes over time. The team envisions EEG becoming a "readily accessible, affordable and longitudinal biomarker of Alzheimer's disease." A biomarker is a measurable biological sign that provides information about a person's health or a particular disease. A longitudinal biomarker can be tracked repeatedly to monitor how a condition develops or changes. "Portable EEG systems could allow us to monitor people in their home environments and potentially screen for changes associated with an Alzheimer's disease, without the initial need for expensive or invasive tests," Macauley said. If future human studies confirm the usefulness of these electrical signatures, portable EEG devices might eventually help doctors identify people who need additional testing. This could be particularly valuable in rural communities across Kentucky, where patients sometimes must travel long distances to reach specialized medical centers. Instead of requiring every potentially at-risk patient to undergo advanced testing immediately, local clinics might use simpler monitoring tools to identify individuals who would benefit from further evaluation. Although this application still requires validation, it offers a possible path toward more accessible Alzheimer's screening and monitoring. Ultimately, the study suggests that treating Alzheimer's may require looking beyond the plaques themselves and examining how the brain responds to them. By identifying the immune cells responsible for much of the sleep disruption in their mouse models, the University of Kentucky researchers have uncovered a potential way to restore an essential brain function without first removing the underlying amyloid deposits. The next challenge is determining whether calming these cells can deliver similar benefits in people, potentially improving sleep, cognition and quality of life long before the most severe symptoms of Alzheimer's develop. 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 Medical Sciences 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 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).