Brain immune cells tied to sleep loss in Alzheimer’s mouse study
University of Kentucky researchers restored lost sleep in mice by temporarily reducing microglia, while amyloid plaques remained in place.
By Tom Brennan · Health & Medicine Correspondent
3 min read
University of Kentucky researchers say overactive immune cells in the brain, rather than amyloid plaques alone, drove sleep loss in a mouse model of Alzheimer’s disease. The finding matters because poor sleep is thought to worsen Alzheimer’s-related damage, and the study points to a possible way to treat that disruption without first removing plaques.
The work, published in Alzheimer’s & Dementia, was led by Shannon L. Macauley, an associate professor of physiology in the UK College of Medicine, with first author Nicholas J. Constantino, a recent UK doctoral graduate. According to the university, the team found that microglia, the brain’s resident immune cells, set off inflammation in response to amyloid plaques and interfered with deep sleep.
Researchers used mice genetically prone to developing amyloid plaques and compared them with normal aging mice. They studied the animals at 6 months, when plaques start to appear, and at 18 months, when disease was more advanced.
The team tracked sleep and brain activity using small head-mounted devices that recorded EEG and EMG signals. Those measures allowed the researchers to distinguish wakefulness, nonrapid eye movement sleep and rapid eye movement sleep. They also used light sheet microscopy to map plaques and immune cells in three dimensions across the brain.
To test whether microglia were causing the sleep changes, the researchers gave mice Pexidartinib, or PLX3397, a drug originally developed for cancer research that blocks a survival pathway used by microglia. After 14 days, about 87% of the brain immune cells had been temporarily removed, according to the University of Kentucky.
The result was a gain of more than two hours of sleep per day in mice with Alzheimer’s-related pathology. The animals also had longer stretches of restorative nonrapid eye movement sleep, while their amyloid plaque levels did not change.
Macauley said the study showed that the plaques themselves, or damaged neurons alone, did not explain the sleep deficit. She said microglia responding to plaques appeared to trigger a broader inflammatory reaction that kept the brain awake.
The study also found that sleep disruption did not steadily worsen as plaques increased. Constantino said the sleep and cortical EEG changes seen when plaques first appeared at 6 months did not become worse by 18 months, even though plaque burden had more than doubled.
According to the researchers, that pattern suggests an early immune response may be enough to produce a lasting sleep deficit. Normal aging mainly reduced REM sleep in the study, while amyloid pathology was linked to loss of NREM sleep, the stage Macauley described as important for repair, learning, memory and waste clearance.
The researchers are not proposing that microglia should be broadly eliminated in people. Macauley’s lab is now studying whether existing drugs, including the diabetes drug metformin and the antiseizure drug stiripentol, can calm microglial activity without removing the cells.
The team also identified EEG patterns that may help separate Alzheimer’s-related changes from normal aging. Macauley said portable EEG systems could eventually help monitor people at home and screen for Alzheimer’s-associated changes before more expensive or invasive testing is needed.
The research was supported by the National Institute on Aging, the National Institute of General Medical Sciences, the Cure Alzheimer’s Fund and The CART Fund, according to the University of Kentucky.
This story draws on original reporting from ScienceDaily.