Brain’s ability to clear Alzheimer’s protein linked to circadian cycle

The brain’s ability to clear a protein closely linked to Alzheimer’s disease is tied to our circadian cycle, according to new research that underscores the importance of healthy sleep habits and opens a path to potential Alzheimer’s therapies.

The brain’s ability to clear out a protein that has previously been closely linked to Alzheimer’s disease is connected to our circadian cycle, according to research published in PLOS Genetics. The research not only shows just how important healthy sleep habits could be in preventing the protein Amyloid-Beta 42 (AB42) from forming clumps in the brain, but could lead the way to potential Alzheimer’s therapies.

Longevity.Technology: Alzheimer’s disease is multifactorial, with various risks and multiple pathways. Given that there is currently no known cure, research that can lead to therapies that slow, halt or even prevent this devastating neurodegenerative disease are crucial. Sleeping is already linked to the disease: an increase in the amount of time spent sleeping is a common feature of later-stage Alzheimer’s. As it progresses, the disease causes more extensive damage to a person’s brain, resulting in them becoming weaker and frailer over time and needing more and more sleep. Now new research shows that healthy sleep habits are perhaps even more important that first suspected.

“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 [1].”

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 [1].

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

A tell-tale sign of Alzheimer’s disease is plaques, formed when AB42 protein pieces clump together; these toxic plaques collect between the neurons and disrupt cell function. Macrophages (referred to as microglia when they reside in the brain), are immune cells that seek and destroy unwanted material; they clear AB42 from the brain by ingesting via phagocytosis.

In earlier research, Dr Hurley and collaborators at the Royal College of Surgeons in Ireland investigated circadian control of macrophages, amassing an enormous dataset that made it possible to determine 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 [2].

The team set out to discover whether these cell surface proteoglycans provide a link between the circadian system and Alzheimer’s. In a series of neat experiments to test this hypothesis, the team ascertained 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 implies that the proteoglycans inhibit AB42 clearance [3].

“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 [1].”

The researchers hope that this relationship could be leveraged 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.

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