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.