- People with Alzheimer’s disease often experience sleep disturbances, or circadian disruption.
- This disruption may increase the severity of Alzheimer’s disease.
- A new study suggests that circadian rhythms control the buildup of a key protein in the brain of people with Alzheimer’s.
- The researchers propose that controlling circadian rhythms in people with Alzheimer’s may help alleviate symptoms.
Dementia is one of the leading causes of death worldwide. The most common form, Alzheimer’s disease (AD), affects 1 in 9 people aged 65 and over in the United States and 1 in 14 in this age group in the United Kingdom.
A feature of AD is a disruption in circadian rhythms, the daily physical, mental, and behavioral changes that control our sleep and wakefulness.
Indeed, people can experience sleep disturbances, which are associated with more severe symptoms, years before receiving an AD diagnosis.
Now, researchers from the Rensselaer Polytechnic Institute in New York may have discovered a link between these circadian disruptions and the development of AD.
They carried out their research, which appears in PLOS Genetics, in a laboratory, using cells derived from mouse white blood cells. The researchers identified a molecular mechanism that may be responsible for the connection between AD and circadian rhythms.
Alzheimer’s is a neuroinflammatory disease characterized by the buildup of beta-amyloid. The most damaging of these is beta-amyloid 42 (Aβ42). The proteins form plaques that collect between neurons and disrupt cell function.
Scientists believe the growth of amyloid plaques is a crucial step in the development of AD.
Immune cells called microglia play a role in clearing amyloid plaques. This process, called phagocytosis, is essential for maintaining healthy neurons.
Using mouse cells, the researchers found that phagocytosis changes throughout the day and night. When phagocytosis is interrupted, for example, by sleep disruption, Aβ42 builds up.
People with AD experience a range of symptoms, including memory loss, confusion, delusions, and impulsive behavior. There is a strong association between the buildup of plaques and the development of AD, but it is not yet clear whether the plaques cause the symptoms.
However, scientists think that amyloid plaques accelerate the development of tau tangles, which further damage neurons. Many Alzheimer’s symptoms are due to neuronal damage.
Dr. Percy Griffin, Ph.D., the director of scientific engagement at the Alzheimer’s Association, welcomed the findings. He told Medical News Today:
“Immune cells in the brain are known to clear amyloid, which is one of the hallmarks of Alzheimer’s. The researchers found that the timing of expression of certain molecules on immune cells helps time the uptake and clearance of amyloid.”
Decreased plaque clearance
The researchers found that molecules on the cell surface called heparan sulfate proteoglycans — commonly known as heparan — were key to the phagocytosis of Aβ42.
Dr. Jennifer Hurley, the corresponding author on the study, told MNT: “The presence of heparan sulfate proteoglycans on the cell surface correlated with a decrease in phagocytosis, therefore, heparan sulfate proteoglycans inhibit the phagocytosis of [beta-amyloid].”
These heparan molecules respond to circadian rhythms, with the number of molecules fluctuating during the 24-hour cycle. The researchers found that when heparan levels were higher, phagocytosis of Aβ42 decreased.
To confirm their findings, the researchers broke down heparan using an enzyme. Phagocytosis of Aβ42 then increased.
“Although there are associations between daily rhythms and Alzheimer’s, the mechanisms underlying this relationship are not fully understood. This is an exciting but preliminary study investigating the rhythmic timing of amyloid clearance by immune cells. That being said, this research is done in mice and the findings need to be replicated in humans.”
– Dr. Percy Griffin.
Therefore, the sleep disruption that is common in AD may affect heparan levels. This, in turn, affects the accumulation of amyloid plaques.
The researchers suggest that controlling circadian rhythms may help control inflammatory conditions such as AD.
“As we age, and more so in Alzheimer’s patients, this rhythm disappears,” Dr. Hurley explained to MNT. “This loss could lead to the increase of [beta-amyloid] in the brain.”
“If we could stimulate [beta-amyloid] clearance in aging [brains and those of people with Alzheimer’s] to occur at the right time of day, through simple things like chronotherapeutic administration of light or complex things like immune cell activation or the regulation of heparan sulfate levels, we might be able to reduce the amyloid burden.”
Having identified this molecular mechanism, the researchers are keen to investigate further.
“Our future goals are to understand how this regulation occurs, so that we can find a way to control it therapeutically. We are also investigating the effect that disrupting the circadian clock has on developing Alzheimer’s disease.”
– Dr. Jennifer Hurley.
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