After taking an undergraduate course in circadian rhythms, Marilyn Duncan, PhD, became fascinated with how internal rhythms regulate daily sleep-wake rhythms and many aspects of health and disease.  She said that at the time, courses centered on circadian rhythms and sleep were relatively uncommon, but as knowledge in this field has expanded, many more courses are now available, including one that she now teaches at UK with Bruce O’Hara, PhD, professor of biology.

As a professor of neuroscience at the UK College of Medicine, Dr. Duncan has conducted research investigating the mechanisms underlying age-related alterations in circadian rhythms. Most recently, she has teamed with four fellow principal investigators from UK to spearhead a five-year National Institute on Aging (NIA)-funded pre-clinical investigation of the underlying biological mechanisms linking sleep disruption and the risk and progression of Alzheimer’s disease.

The NIA-funded study is led by experienced faculty in the UK colleges of medicine, arts and sciences, and engineering. The team includes Dr. Duncan and Dr. O’Hara; Adam Bachstetter, PhD, associate professor of neuroscience; Michael Paul Murphy, PhD, professor of molecular and cellular biochemistry; and Sridhar Sunderam, PhD, associate professor of biomedical engineering.

Many prior studies have shown that the disruption of daily sleep cycles can make a person more likely to face Alzheimer’s disease. “And it isn't just sleep loss,” Dr. Duncan said. “It is also the breakdown of the daily biological rhythms” that can factor into disease progression.

Through their NIA study, UK researchers are using AD-like mouse models to study the effects of sleep fragmentation on the brain. One of their methods – which was recently published in Neuroscience – involved allowing female AD-model mice to sleep undisturbed while others were subjected to chronic sleep fragmentation. The latter mice group underwent four daily one-hour sessions of enforced wakefulness, evenly distributed during the light phase, five days a week for four weeks. This protocol altered the daily sleep-wake rhythm, with increasing fragmentation and redistribution of sleep such that more occurred during the normal active phase and less during the typical rest phase. 

“And sure enough, the brains from the mice that had this sleep fragmentation protocol had increased neuropathology in the hippocampus, which is a brain region critical for memory,” Dr. Duncan said, “After sleep fragmentation, Dr. Murphy measured elevated levels of amyloid beta 42, which is considered especially neurotoxic, and Dr. Bachstetter detected higher levels of neuroinflammatory markers.” 

In contrast to these sleep fragmentation-induced changes in the hippocampus, no changes were observed in the cortex, which is responsible for executive functions such as planning, prioritization, and organization. This suggests that the cortex is less vulnerable than the hippocampus to the detrimental effects of sleep fragmentation, at least during this four-week time frame.

Dr. Duncan said that intriguingly, the hippocampus also appears to be selectively sensitive to the beneficial effects of sleep enhancement.  When Dr. Sunderam exposes AD-model mice to thermoneutral warming in his lab, he observes selective increases in deep (slow-wave) sleep that are accompanied by decreases in amyloid-beta levels in the hippocampus but not the cortex. These and other studies suggest that consolidating the daily rhythm of sleep-wake and enhancing deep sleep may be strategies for decelerating the progression of AD neuropathological changes. Ongoing investigations include sex differences in sleep patterns and responses to sleep fragmentation and the effects of sleep fragmentation on gene expression and metabolism.

The NIA study is funded through 2025. It will not only expand the public’s knowledge of biological mechanisms underlying the link between sleep disruption and neurodegeneration, but also provides learning opportunities for at least a dozen trainees, including graduate students, postdoctoral fellows, and undergraduate students pursuing careers in neuroscience-related research.

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG068215. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.