This treatment promises to improve sleep in people with Alzheimer's.

A team led by scientists at the University of Kentucky (United States) claims to have recovered more than two hours of sleep per night in Alzheimer's model mice, without eliminating the amyloid plaques that form in the brain in connection with the disease. In a statement, the researchers explain their findings with a simple example: "Imagine a small isolated fire in your kitchen. If you had the right tool, you could put it out. But before you can do so, the sprinklers activate and flood the entire house. An automatic response to a problem ends up damaging everything you own." "Something similar happens in the brains of people with Alzheimer's: amyloid plaques, sticky protein accumulations that form in the brain, are the fire in the kitchen. Microglia, the set of resident immune cells in the brain, act as the sprinklers. A mechanism designed to protect the body ends up causing it harm." The researchers, who published their findings in the journal Alzheimer's & Dementia, maintain that microglia is the main factor in the sleep loss associated with the disease. They claim that by using a drug to temporarily eliminate these cells in model mice, they managed to recover more than two hours of sleep per night. The findings open a new therapeutic avenue for treating the disease, the study authors state. Associate Professor of Physiology at the University of Kentucky College of Medicine, Dr. Shannon L. Macauley, led the research. She describes the results as a "paradigm shift." Although previous studies have determined that sleep loss in Alzheimer's is a consequence of neuronal death or the physical accumulation of amyloid plaques, the results of the recent research suggest that the problem is rather due to a "reaction that affects the whole house." "Basically, we have shown that sleep loss is not due to the plaques themselves, nor solely to neuronal dysfunction, but to microglia. Microglia are immune cells that, by reacting to the plaques, trigger a complex inflammatory cascade. It is as if these cells were partying all night, keeping the brain in a state of wakefulness," explains Dr. Macauley. This treatment promises to improve sleep in people with Alzheimer's, according to a preliminary trial. Photo: U. of Kentucky. Jeremy Blackburn How hours of sleep were recovered in Alzheimer's without eliminating amyloid plaques, according to the study To isolate the effects of Alzheimer's from the natural changes associated with aging, the scientists compared two groups of mice. One consisted of mice with a genetic predisposition to develop amyloid plaques. The other, the control group, consisted of "wild-type" mice, without genetic modifications, that aged naturally. The team studied the groups at six months of age, when the first plaques appear, and at 18 months, which represents an advanced stage of the disease. The researchers employed various sophisticated technological techniques to carry out monitoring: they placed small devices on the mice's heads to record electroencephalograms (EEG) and electromyograms (EMG). They explain that an EEG functions like an "electrical fingerprint" of the brain, recording the unique patterns of electrical activity and the oscillations generated by brain networks. An EMG, for its part, records muscle movement. This allowed the team to determine precisely when the mice were in a phase of deep, restorative sleep, in the dreaming phase of sleep, or in a state of wakefulness. Dr. Macauley details that to observe where the immune cells were "partying all night," in her words, they used a cutting-edge technique called light sheet microscopy. This procedure involves making the brain tissue transparent and using a thin sheet of laser light to generate a high-resolution digital 3D map. With this, they were able to visualize the entire panorama of plaques and immune cells simultaneously. To identify microglia as the cause of sleep loss, they used a drug called pexidartinib (PLX3397). That medication, originally used in oncology research, works by blocking a signal that microglia needs to survive. The team reports that, by administering this drug to the mice for 14 days, they managed to temporarily eliminate 87% of the brain's immune cells, in order to check whether sleep was recovered. In Dr. Macauley's words, the findings are "surprising and unexpected." This treatment promises to improve sleep in people with Alzheimer's, according to a preliminary trial. Photo: U. of Kentucky. The study's first author, Dr. Nicholas J. Constantino, states: "I expected that, as plaque burden became more severe, sleep disruption would also worsen." "The alterations in sleep and in cortical electroencephalographic activity observed at six months — the moment when the first plaques appear — did not worsen at 18 months, even though the plaque burden had more than doubled." The researchers describe the above as a "ceiling effect," since even when plaque levels increased to more than double, the sleep deficit remained stable. But the most significant finding for the team was the result of the elimination of microglia: by removing these immune cells, the Alzheimer's mice managed to sleep more than two additional hours each night. Their periods of restorative sleep lengthened, giving them more opportunities to enter the sleep phase associated with dreaming, which is essential for the formation of new memories. The authors emphasize that sleep was recovered without altering the amount of amyloid plaques in the brain, which, they maintain, suggests that the body's inflammatory response is a reversible cause of sleep loss, one that can be treated independently of the presence of these plaques. The team expects that their findings will serve as a basis for future research and could contribute to the development of affordable and non-invasive tools for patients with Alzheimer's disease. "Portable EEG systems could allow us to monitor people in their own home environment and, potentially, detect changes associated with Alzheimer's disease, without initially needing to perform costly or invasive tests," proposes Dr. Macauley. According to the University of Kentucky academic, this would make it easier for doctors to screen people at risk, sparing them from having to travel for hours to undergo more specialized examinations at large hospitals. Currently, her laboratory is investigating how to "calm" these immune cells without eliminating them completely. She reports that they are exploring the use of existing and safe medications to readjust the way microglia uses its "fuel" and reduce its hyperactivity. By preventing these immune cells from overstimulating the brain's "engine," says Dr. Macauley, they hope to achieve restored sleep and improved quality of life, years before memory loss begins. "If we manage to intervene in that process, we could help improve quality of life, care, cognitive ability, and states of confusion," she emphasizes.