Immune cells that clear away Alzheimer's disease protein are controlled by circadian rhythms

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Greyhound
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Immune cells that clear away Alzheimer's disease protein are controlled by circadian rhythms

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The findings provide a mechanism that links Alzheimer's disease with circadian rhythm disruptions
Peer-Reviewed Publication

PLOS
Immune cells that clear away Alzheimer's disease protein are controlled by circadian rhythms

image: Image Caption: The image of a clock with brightfield macrophage images around it shows how circadian changes of cell surface heparan sulfate proteoglycans, shown in pink, impedes phagocytosis of fluorescently labeled amyloid-beta, shown in green. As time goes on, and we have a reduction in heparan sulfate proteoglycans, we see an increase in phagocytosis, demonstrated by the bright green cells shown on the left of the clock. This image was made using our fluorescent microscopy cell images with an artistic rendering of the heparan sulfate proteoglycans from the app, Wombo. The clock was made using photoshop and clip art. view more

Credit: Gretchen Clark, made using Wombo (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)

Researchers report that the immune cells responsible for clearing away a key protein that builds up in the brains of patients with Alzheimer's disease operate according to daily circadian rhythms. The discovery, reported by Jennifer Hurley of Rensselaer Polytechnic Institute and colleagues in a new study publishing February 10th in the journal PLOS Genetics, provides a potential explanation for the link between Alzheimer's disease and disruptions to a person's sleep cycle.

Alzheimer's disease is known to be associated with disruptions in circadian rhythms, the 24-hour cycle that controls many aspects of human behavior and physiology. For example, sleep disruptions begin years before symptoms of Alzheimer's disease appear and are linked to more severe symptoms and a higher risk of developing the disease.

In the new paper, researchers investigated a molecular mechanism potentially responsible for the connection between Alzheimer's disease and circadian rhythms. They measured the activity of immune cells responsible for clearing away proteins called amyloid-beta that build up as plaques in the brains of people with Alzheimer's disease. Using cultures of these cells grown in the lab, they discovered that the immune cells clear away the amyloid-beta on an oscillating daily cycle controlled by circadian rhythms. However, when cells lost that rhythm, the daily cycle disappeared. They further established that the underlying cause of this oscillation was changes in the number of molecules of a certain protein, heparan, on the cell's surface. The protein they identified responds to circadian rhythms and previously had been shown to play a role in clearing amyloid-beta proteins.

The new findings uncover a mechanism that links the disruption of circadian rhythms to Alzheimer's disease. The study further highlights the role of immune cells in this relationship. While more studies will be necessary, the new findings present the possibility that, if the daily clearance of amyloid-beta proteins through this mechanism can be maintained, patients may be less likely to develop Alzheimer's disease and to exhibit less severe symptoms.

Hurley adds, “Understanding how our circadian rhythms can regulate cell-surface heparan levels to control the build-up of amyloid-beta may lead to the development of chronotherapeutics that alleviate the symptoms of Alzheimer’s Disease as well as other inflammatory diseases.”

https://www.eurekalert.org/news-releases/942364

Clearance of protein linked to Alzheimer’s controlled by circadian cycle

Ability of immune system to destroy Alzheimer’s-related protein oscillates with daily circadian rhythm
Peer-Reviewed Publication

Rensselaer Polytechnic Institute
Circadian control

image: Circadian rhythms control the removal of a key protein linked to Alzheimer's disease. view more

Credit: Rensselaer Polytechnic Institute

TROY, N.Y. — The brain’s ability to clear a protein closely linked to Alzheimer’s disease is tied to our circadian cycle, according to research published today in PLOS Genetics. The research underscores the importance of healthy sleep habits in preventing the protein Amyloid-Beta 42 (AB42) from forming clumps in the brain, and opens a path to potential Alzheimer’s therapies.

“Circadian regulation of immune cells plays a role in the intricate relationship between the circadian clock and Alzheimer’s disease,” said Jennifer Hurley, an expert in circadian rhythms, and associate professor of biological science at Rensselaer Polytechnic Institute. “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 research was conducted at the Rensselaer Center for Biotechnology and Interdisciplinary Studies, which has a focus on neurodegenerative disease. Dr. Hurley worked with Rensselaer professors Robert Linhardt, a glycans expert and inventor of synthetic heparin, and Chunyu Wang, whose ongoing research has detailed several mechanisms in the production and spread of proteins implicated in Alzheimer’s.

“This insight reveals a new mechanism and path to treatment of neurodegenerative diseases like Alzheimer’s through an interdisciplinary approach, and is emblematic of the CBIS strength in research and discovery and provides a new angle to human health and well-being,” said Deepak Vashishth, director of the CBIS.

The circadian system is comprised of a core set of clock proteins that anticipate the day/night cycle by causing daily oscillations in the levels of enzymes and hormones, ultimately affecting physiological parameters such as body temperature and the immune response. Disruption of the circadian system is increasingly associated with diseases like diabetes, cancer, and Alzheimer’s.

A telltale sign of Alzheimer’s disease is plaques, extracellular clumps of AB42 in the brain. Macrophages (referred to as microglia when they reside in the brain), which are immune cells that seek and destroy unwanted material, clear AB42 from the brain by ingesting it in a process called phagocytosis. In earlier research, Dr. Hurley and collaborators at the Royal College of Surgeons in Ireland investigated circadian control of macrophages, amassing an exhaustive dataset that made it possible to see which macrophage RNA and proteins oscillate with a circadian rhythm. The researchers noticed oscillations in enzymes that help to make two proteins on the macrophage cell surface – heparan sulfate proteoglycan and chondroitin sulfate proteoglycan– both of which are known to play a role in regulating clearance of AB42.

Could these cell surface proteoglycans be a link between the circadian system and Alzheimer’s? In a series of elegant experiments testing this hypothesis, the team established that the amount of AB42 ingested by healthy macrophages oscillates with a daily circadian rhythm. That pattern did not occur in macrophages without a circadian clock. They also measured daily oscillations in the levels of heparan sulfate proteoglycans and chondroitin sulfate proteoglycans produced on the surface of macrophage cells with healthy circadian cycles. Peak AB42 clearance occurred as production of surface cell proteoglycans was at its lowest level, and removal of these proteoglycans increased ingestion, which suggests that the proteoglycans inhibit AB42 clearance.

“What’s clear is that this is all timed by the circadian clock,” said Dr. Hurley. “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.”

That relationship could be used to develop therapies that would encourage greater AB42 clearance, perhaps by boosting the amplitude of daily oscillations, which tend to diminish as we age.

“In theory, if we could boost that rhythm, perhaps we could increase the clearance of AB42 and prevent damage to the brain,” said Dr. Hurley.

At Rensselaer, Hurley, Linhardt, and Wang were joined in the research by Gretchen T. Clark, Yanlei Yu, Cooper A. Urban, Fuming Zhang, and Guo Fu, who is now at the Chinese Academy of Sciences. “Circadian Control of Heparan Sulfate Levels Times Phagocytosis of Amyloid Beta Aggregates” was produced with support from the National Institutes of Health, the National Science Foundation, and the Warren Alpert Foundation.
https://www.eurekalert.org/news-releases/942776
good t
Two related releases are the same....good to know how this works now!
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