The Ma Tong Hypothesis of Brain Metabolite Clearance: Circadian Clock Effect on Beta-Amyloid Accumulation

Brain metabolite clearance is one of the key goals for preventing neurodegenerative diseases such as Alzheimer's disease (AD). Using the circadian clock as a target, we seek an alternative method to improve the metabolite clearance efficiency. In our recent work, we found that the choroid plexus (CP) hosts the strongest circadian clock in the murine brain. The cerebrospinal fluid undergoes timed production by the CP's own local clock, independently of the sleep state most dominantly controlled by the suprachiasmatic nucleus (SCN) in mice. In addition to sleep, which has been shown to cause metabolite 'drainage', our finding suggests an additional player in this systemic homeostasis: the 'production' of metabolite dilution medium. We show that the phase of the CP's circadian clock relative to the SCN's can determine the metabolite clearance efficiency of the brain, and that this relative phase can be manipulated by the day length. Our preliminary modeling prediction and experimental results using model mice of AD align with epidemiological findings that AD is more prevalent in high latitudinal locations. In this project, we aim to clarify this novel mechanism of systemic metabolite clearance and help define clinical strategies for the prevention of AD.