University of Kentucky Researchers Discover Link Between Microglia and Sleep Loss in Alzheimer's

Lead researcher Shannon L. Macauley, Ph.D., along with first author Nicholas J. Constantino, Ph.D., found that microglia, the brain's immune cells, are the primary contributors to sleep disruption in an animal model of Alzheimer's. When the research team used a drug, Pexidartinib, to temporarily eliminate about 87% of these cells, the mice regained over two hours of sleep each night, indicating a potential new treatment avenue for the disease, which Macauley described as "paradigm shifting."

Previous studies attributed sleep loss in Alzheimer's primarily to damaged neurons or the presence of amyloid plaques. However, the new findings suggest that microglia's inflammatory response to plaques could be more critical, likening their action to a sprinkler system responding to a small fire, which unwittingly causes greater damage.

To distinguish between changes due to Alzheimer's and those related to normal aging, the researchers examined two groups of mice at different ages—six months, when plaques appear, and 18 months, when the disease is more advanced. By employing advanced monitoring techniques for sleep and brain activity, they were able to pinpoint the disturbances caused by microglia.

Macauley emphasized that the accumulation of amyloid plaques does not necessarily worsen sleep disruption as mice age. In fact, even though plaque levels doubled from six to 18 months, sleep lost consistently remained the same, suggesting that early immune responses to initial plaque formation are sufficient to establish sleep problems.

The study also highlighted that while normal aging reduces REM sleep, Alzheimer's primarily affects non-REM sleep, crucial for brain restoration and waste clearance. This sustained loss of restorative sleep may disrupt the brain's ability to clear toxins and further exacerbate the disease.

Notably, once microglia were depleted, the mice experienced substantial improvements in sleep duration and quality without any changes to plaque levels, implying that targeting the inflammatory response could be a separate approach from addressing plaque accumulation.

The research environment fostered by Macauley's laboratory encouraged collaborative inquiry and risk-taking, which she believes is essential for scientific advancement. Future work aims to develop non-invasive EEG technologies to monitor brain activity linked to Alzheimer's and potentially discover effective treatments that calm microglia activity without complete removal.

This study was supported by multiple grants from the National Institutes of Health and private funding from organizations committed to Alzheimer's research.