Summary: Restoring normal sleep patterns by activating the thalamic reticular nucleus (TRN) with chemogenetic tools reduced the accumulation of amyloid-beta plaques in the brain in an animal model of Alzheimer’s disease.
Source: Baylor College of Medicine
Multiple studies in humans and in mouse models indicate that sleep disruption raises the risk of Alzheimer’s disease (AD) by promoting accumulation of disease-relevant proteins such as amyloid-beta (Aβ) in the brain.
In a new study led by researchers at Baylor College of Medicine, restoring normal sleep by reactivating the thalamic reticular nucleus (TRN)—a brain region that helps maintain stable sleep—reduced Aβ plaque accumulation in an AD mouse model. The results, published in Science Translational Medicine, suggest that TRN dysfunction may drive sleep problems seen in AD and that restoring TRN activity could be a potential therapeutic approach.
The TRN is less active in Alzheimer’s models
“Our interest in the TRN came after observing reduced TRN activity in an animal model of Alzheimer’s disease compared with animals without the condition,” said corresponding author Dr. Jeannie Chin, associate professor of neuroscience at Baylor College of Medicine.
Normally, the TRN becomes more active during sleep than during wakefulness. This increased activity helps suppress peripheral sensory signals—like sounds and lights—so that we remain less aware of the environment and can maintain restful sleep. When TRN activity is reduced, those protections are weakened and sleep becomes fragmented.
First author Dr. Rohan Jagirdar, an instructor in the Chin lab, explained that the team tested whether reduced TRN activity could explain sleep interruptions commonly observed in people with AD. Using a wireless system to record brain activity, the researchers found that the Alzheimer’s model mice woke up 50% more often during normal sleep hours than non-AD controls. These AD mice also spent less time in slow-wave sleep (SWS), the deep restorative phase when the brain clears metabolites and waste products. These sleep changes appeared early, before memory deficits emerged.
“This is relevant to humans because sleep fragmentation and other sleep disturbances in cognitively normal people are associated with higher Alzheimer’s risk,” Chin said. As the AD mice aged to three to five months, sleep disruption persisted and memory problems emerged, mirroring disease progression.
Reduced TRN activity correlates with Aβ plaque burden
In the mouse model, measurable Aβ appeared around one month of age and began forming plaques by about six months. The team examined whether early sleep fragmentation and reduced SWS were linked to the later accumulation of plaques. At six to seven months, mice with greater sleep fragmentation had higher Aβ plaque loads in the brain.
These findings indicate that sleep disruptions in AD models may contribute to the buildup of disease-related proteins. To extend the findings to humans, the researchers analyzed postmortem brain tissue from individuals with Alzheimer’s disease, mild cognitive impairment, or no cognitive impairment. As in mice, neurons in the TRN from Alzheimer’s patients showed signs of reduced activity, and patients with the least active TRN had the highest Aβ plaque deposition. These results support a relationship between diminished TRN function and increased accumulation of AD-associated proteins.
Reactivating the TRN improves sleep and lowers Aβ
To test whether restoring TRN function could improve sleep and reduce Aβ accumulation, the team used chemogenetics—a method that permits targeted chemical activation of specific neurons—to selectively stimulate TRN cells in the AD mouse model. After a single chemogenetic activation, AD mice woke less frequently and spent more time in slow-wave sleep, indicating improved sleep architecture.
“Excitingly, daily chemogenetic activation of the TRN for one month produced sustained TRN activation, consistent improvements in sleep, and a marked reduction in Aβ accumulation,” Chin said. The researchers caution that not all forms of sleep disturbance stem from TRN dysfunction; conditions such as obstructive sleep apnea or restless leg syndrome arise from different causes and may not respond to TRN-targeted interventions.
“Our findings indicate that selective activation of the TRN could be a promising therapeutic strategy to improve sleep disturbances and slow Aβ accumulation in Alzheimer’s disease,” Chin added. Additional contributors to the research include Chia-Hsuan Fu, Jin Park, Brian F. Corbett at Baylor College of Medicine, and Frederik M. Seibt and Michael Beierlein at McGovern Medical School at UTHealth Houston.
Funding: Support for this work came from the Ruth K. Broad Biomedical Research Foundation, National Institutes of Health (NIH) grants NS085171 and AG065290, the Neurodegeneration Consortium, and the Belfer Family Foundation. Additional support was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH under Award Number P50HD103555.
About this sleep and Alzheimer’s disease research news
Author: Graciela Gutierrez
Source: Baylor College of Medicine
Contact: Graciela Gutierrez – Baylor College of Medicine
Image: The image is in the public domain
Original Research: Closed access. “Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice” by Jeannie Chin et al., Science Translational Medicine
Abstract
Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice
Sleep disruption promotes increases of amyloid-β (Aβ) and tau in the brain and raises Alzheimer’s disease (AD) risk, but the specific mechanisms that drive sleep disturbances are not fully defined. The thalamic reticular nucleus (TRN) is essential for maintaining sleep and regulating slow-wave sleep (SWS), the phase linked to restorative processes and metabolite clearance.
In transgenic mice expressing mutant human amyloid precursor protein (APP), the authors found reduced neuronal activity in the TRN, increased sleep fragmentation, and decreased time in SWS compared with nontransgenic littermates. Selective activation of the TRN using excitatory DREADDs restored sleep maintenance, increased SWS duration, and reduced amyloid plaque load in hippocampus and cortex. These findings suggest the TRN may play a major role in symptoms associated with AD and that enhancing TRN activity might represent a promising therapeutic strategy.