The endogenous 24-hour cycle controls human behaviour and cell physiology. Disruptions in this cycle have been linked to an increase in both the prevalence and severity of Alzheimer's disease. About three years ago, we reported on an early study showing that the sleep-wake cycle affects tau levels.1
A recent paper takes this a step further. Seeking to understand the mechanistic link between disruptions of the circadian system and Alzheimer's disease, researchers studied the diurnal activity of immune cells that are responsible for the clearance of amyloid-beta (Aβ42). They discovered that one key component in the Aβ metabolism undergoes circadian regulation.2
The scientists proved in cell cultures that macrophages (or microglia in the brain) break down amyloid-beta in an oscillating daily cycle that is controlled by the circadian rhythm. Once the cells lost this rhythm, the diurnal cycle vanished.
The underlying cause of this oscillation was found to be the accumulation of certain molecules on the cell surface: heparan sulphate proteoglycans and chondroitin sulphate proteoglycans, which had previously been shown to respond to circadian rhythms and to play a role in regulating the breakdown of Aβ42.
This phenomenon was specific to Aβ42, explaining the link between disrupted day-night rhythms and the risks of the accumulation of misfolded proteins.
Aβ42 clearance peaked when the expression of surface proteoglycans was at its lowest. Removing these proteoglycans resulted in increased phagocytosis, suggesting that the proteoglycans inhibit Aβ42 ingestion.
"Understanding how our circadian rhythms manage heparan levels on the cell surface to regulate the production of amyloid beta could lead to the development of chronotherapeutics that would help reduce the symptoms of Alzheimer's disease and other inflammatory diseases," says the research group's leader, Dr Jennifer Hurley of Rensselaer Polytechnic Institute, New York State, in a hopeful remark.3
Based on their findings, new therapies could encourage the breakdown of Aβ42, perhaps by increasing the amplitude of daily oscillations (which decreases as we age). "In theory, if we could amplify this rhythm, we might be able to increase the clearance of Aβ42 and prevent damage to the brain," Dr Hurley said.4
Alzheimer's disease is presently an incurable, costly, and ever-increasing neurodegenerative disease that affects millions of people. There is a bidirectional relationship between the disease and circadian system disorders, with sleep disturbances often occurring years before the onset of Alzheimer's symptoms and with more severe symptoms and a higher risk of developing the disease.
In the prevention of Alzheimer's disease, as well as in the treatment of early stages, it may be helpful to have interventions that restore circadian rhythms, which, in addition to regular bedtimes, could include a reduction in blue light exposure from backlit devices, especially after sunset, and possibly melatonin supplements.
Dr Richard Isaacson, director of the Alzheimer's Prevention Clinic at Weill Cornell Medical College and director of the Weill Cornell Memory Disorders Program and author of several New York Times bestsellers on Alzheimer's, has been stressing the importance of this link for many years. "Exercise and sleep are simply two of the most important things." In his view, a key factor is also diet as well as vital parameters such as resting heart rate and heart rate variability.5
References:
1. Clark, G. T. et al. Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates. PLOS Genetics 18, e1009994 (2022).
2. Immune cells that clear away Alzheimer’s disease protein are controlled by circadian rhythms – BioNews Central.
3. Martialay, M. L. Clearance of Protein Linked to Alzheimer’s Controlled by Circadian Cycle.
4. Labs, D. I. Dr. Richard Isaacson & Alzheimer’s Prevention | WHOOP Podcast. WHOOP