Restoring normal sleep reduces amyloid beta accumulation in the mouse model of Alzheimer’s disease

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Sleep Health | Sleep Review

Several studies in humans and mouse models indicate that sleep disorders increase the risk of Alzheimer’s disease (AD) by increasing the accumulation of disease-related proteins such as amyloid-beta (A-beta) in the brain. In the current study, a team led by researchers from Baylor College of Medicine discovered that in an animal model of Alzheimer’s disease, normal sleep is restored by increasing the activity of the thalamic reticular nucleus (TRN), a region of the brain that is involved in maintaining it the stable sleep, reduced the accumulation of A-beta plaques in the brain.

The study, published in the journal Science Translational Medicine, suggests that not only could the thalamic reticular core play an unprecedented driving role in the symptoms of Alzheimer’s, but that restoring its normal activity could be a potential therapeutic approach for this serious condition could.

Thalamus-reticular nucleus is quiet in Alzheimer’s disease

“Our interest in studying TRN in connection with Alzheimer’s disease began when we observed in an animal model that TRN activity was generally reduced compared to the TRN activity of animals without the disease,” says the corresponding author Jeannie Chin, PhD, Associate Professor of Neuroscience at Baylor, in a press release.

When we sleep, the thalamic reticular core is generally more active than when we are awake, Chin says. This increased TRN activity reduces the perception of peripheral sensory information. As a result, we usually do not perceive sounds, lights, and other sensations during sleep, which helps us sleep well.

“Since we observed that the TRN was less active in our animal model than in animals without the disease, we investigated the possibility that a quiet TRN could be a reason for the frequent sleep interruptions in people with Alzheimer’s disease,” says lead author Rohan Jagirdar , PhD, an instructor in the Chin Laboratory.

The researchers began by determining whether their Alzheimer’s disease mice would wake up more often during normal sleep times than mice without the disease. Using a wireless system that recorded the animals’ brain activity, the researchers discovered that Alzheimer’s mice actually woke up 50% more often than non-Alzheimer’s mice. In addition, the Alzheimer’s mice received less than the normal amount of slow-wave sleep, the deep restful sleep that removes waste products and metabolic products from the brain. This was seen in the early stages of the disease, before the animals developed memory deficits.

“This finding is relevant to the human condition, as research has shown that sleep fragmentation and other sleep disorders in cognitively normal people are associated with an increased risk of Alzheimer’s,” says Chin. “As AD mice got older, reaching around three to five months, their sleep continued to be interrupted and they also exhibited memory deficits.”

Calm thalamic-reticular nucleus associated with A-beta plaque load

In the animal model of Alzheimer’s disease, measurable levels of A-beta began to appear in the brain when the mice were about one month old and began to deposit in plaques by about six months of age.

“We investigated whether the sleep fragmentation and slow sleep reduction that we observed in our AD mouse model could be linked to the accumulation of A-beta in later stages by studying mice six to seven months of age “Says Jagirdar. “We found that the amount of sleep fragmentation was directly related to the plaque load in the brain of six-month-old AD mice.”

Taken together, these results show that AD mice have sleep disorders that could affect the accumulation of proteins that are involved in disease progression.

In addition, Chin, Jagirdar, and their colleagues analyzed post-mortem tissue from patients with either Alzheimer’s disease, mild cognitive impairment, or none of these disorders. They discovered that neurons in the TRN of Alzheimer’s patients, as they had found in the mouse model, were less active compared to the controls. In addition, the brains of AD patients with the least active TRN had the highest A-beta plaque deposition. These results support the possibility of a link between decreased TRN activity and increased accumulation of disease-causing proteins in Alzheimer’s disease.

Could reactivation of the thalamic reticular nucleus improve the condition?

Using a chemogenetic system, a technology that enables certain cells to be chemically activated, the team activated TRN neurons in an animal model. After a single round of chemogenic activation of the TRN, the AD mice woke up less often and spent more time in slow-wave sleep, signs of improved sleep activity.

“It was exciting to see that after receiving chemogenetic activation of TRN daily for a month, the AD mice showed sustained activation of TRN neurons, consistent improvements in sleep and a remarkably reduced accumulation of A-beta” says Chin.

The researchers point out that while this approach appears to improve sleep disorders and A-beta deposition in this mouse model of Alzheimer’s disease, not all sleep disorders affect the thalamic reticular nucleus.

“Sleep disorders are linked to a number of disorders and have different causes,” says Jagirdar. “Targeting the TRN may not be as effective if the sleep disorder is due to unrelated causes, such as: B. Obstructive Sleep Apnea or Restless Legs Syndrome. “

“Our results support that selective activation of the TRN is a promising therapeutic intervention to improve sleep disorders and slow the accumulation of A-beta in AD,” says Chin.

Photo 37514268 © Ross Kummer | Dreamstime.com



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