Healthier sleep habits may be a key to alleviating some of the symptoms of Alzheimer’s disease. The brain’s ability to clear a protein closely linked to Alzheimer’s disease is associated with the human circadian cycle.
The circadian clock system consists of a core set of proteins. The proteins cause oscillations in the body’s levels of enzymes and hormones which affect physiological functions, such as body temperature and the immune response.
Amyloid-Beta 42 (AB42) is the protein associated with Alzheimer’s disease. It forms clumps in the brain, which have a role in Alzheimer’s symptomatology. The brain’s ability to clear the protein from brain tissue is associated with the human circadian cycle, according to recent research. The cycle becomes disrupted years before symptoms develop.
“Circadian regulation of immune cells plays a role in the intricate relationship between the circadian clock and Alzheimer’s disease,” says Jennifer Hurley, an expert in circadian rhythms at the Rensselaer Polytechnic Institute in New York, in a statement. “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.”
The most abundant and best studied of the macrophages are the microglia, which are immune cells that seek and destroy unwanted material. The microglia 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. 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.
The scientists speculated that these cell surface proteoglycans could be a link between the circadian system and Alzheimer’s. Their research established that the amount of AB42 ingested by healthy macrophages oscillates with a daily circadian rhythm.
They also measured daily oscillations in the levels of heparan sulfate proteoglycans and chondroitin sulfate proteoglycans produced on the surface of macrophages with healthy circadian cycles. Peak AB42 clearance occurred when production of surface cell proteoglycans was at its lowest level. The 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,” says 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 encourage greater AB42 clearance. “In theory, if we could boost that rhythm, perhaps we could increase the clearance of AB42 and prevent damage to the brain,” adds Dr. Hurley.
Hurley, Linhardt, and Wang at the Rensselaer Polytechnic Institute collaborated with Gretchen T. Clark, Yanlei Yu, Cooper A. Urban, Fuming Zhang, and Guo Fu, now at the Chinese Academy of Sciences.
This study is published in PLOS Genetics.