Circadian Clocks Role in Regulating Alzheimers-Related Proteins Revealed in New Study

Link Between Alzheimer’s Disease and Circadian Clock

Overview of Alzheimer’s Disease

Alzheimer’s Disease (AD) is primarily marked by a decline in memory capabilities and currently lacks definitive treatment options. A recent study conducted by Rensselaer Polytechnic Institute has uncovered a significant connection between the onset of Alzheimer’s and the circadian clock.

Physiological Characteristics of Alzheimer’s Disease

Alzheimer’s Disease is defined by the accumulation of amyloid-beta proteins (AB) in the form of plaques within the brain. This buildup disrupts normal memory processes, evident in individuals diagnosed with AD. The accumulation of the AB42 protein is particularly critical, as it serves as a diagnostic marker for the disease. Although the mechanism behind this accumulation remains unclear, it is known that the formation of AB plaques is a normal occurrence in healthy adults. Prior research indicates that the quantity of these plaques fluctuates over a 24-hour period in alignment with the circadian clock. However, this rhythm appears to be altered in patients with Alzheimer’s Disease.

Understanding the Circadian Clock

The circadian clock consists of a group of proteins that regulate the levels of various hormones and proteins in accordance with day and night cycles. This daily variation influences immune responses and other physiological functions, including body temperature. Researchers explored the impact of sleep pattern disruptions on the normal fluctuations of AB42 levels in the brain. They utilized bone marrow-derived immune cells, known as macrophages, which typically “consume” AB42 through a process called phagocytosis, to analyze how the circadian clock affects this process.

Circadian Regulation of AB42 Clearance

The research measured the quantity of AB42 ingested by bone marrow-derived immune cells, revealing that the amount varied throughout the 24-hour circadian cycle. Cells lacking a circadian rhythm showed no significant fluctuations in AB42 phagocytosis. Jennifer Hurley, a professor of biological science at Rensselaer Polytechnic Institute and co-author of the study, noted, “This tells us a healthy sleep pattern might be important to alleviate some of the symptoms in Alzheimer’s disease, and this beneficial effect might be imparted by an immune cell type called macrophages/microglia.”

The Role of Heparan Sulfate Proteoglycans

Heparan sulfate proteoglycans (HSPGs) are glycoproteins that play a crucial role in regulating the clearance of AB42 from the nervous system. Researchers investigated the specific influence of HSPGs on AB42 clearance by monitoring the extent of phagocytosis of AB42 by macrophages. Findings indicated that high levels of HSPGs led to reduced phagocytosis, while lower levels resulted in increased consumption of AB42. Hurley remarked, “When there’s a lot of these cell surface proteoglycans, the macrophages don’t ingest the AB42. We’re not certain why that would be, but there is definitely a relationship.” The levels of HSPGs also fluctuated in accordance with the circadian clock.

Implications for Future Alzheimer’s Therapy

This study marks a pioneering identification of the relationship between AB42 clearance, circadian rhythm, and HSPGs. Given that daily circadian oscillations often change with age, developing therapies aimed at regulating these rhythms may offer relief for individuals with Alzheimer’s Disease. Hurley stated, “In theory, if we could boost that rhythm, perhaps we could increase the clearance of AB42 and prevent damage to the brain.” Further research is essential to explore the clinical application of this relationship.

References

Clark, G.T. et al. (2022). Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates. PLOS Genetics. Doi: 10.1371/journal.pgen.1009994.
Huang, Y. et al. (2012). Effects of Age and Amyloid Deposition on AB Dynamics in the Human Central Nervous System. JAMA Neurology; 69(1): 51-58. Doi: 10.1001/archneurol.2011.235.
Martialay, Mary. (2022). Clearance of protein linked to Alzheimer’s controlled by circadian cycle. EurekAlert! Accessed Feb. 15, 2022. Retrieved from https://www.eurekalert.org/news-releases/942776.
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