Abstract
Alzheimer’s Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (Aβ). AD has a bi-directional relationship with circadian disruption (CD) with sleep disturbances starting years before disease onset. However, the molecular mechanism underlying the relationship of CD and AD has not been elucidated. Myeloid-based phagocytosis, a key component in the metabolism of Aβ, is circadianly-regulated, presenting a potential link between CD and AD. In this work, we revealed that the phagocytosis of Aβ42 undergoes a daily circadian oscillation. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of Aβ and that both HSPG binding and aggregation may play a role in this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD.
Highlights
Alzheimer’s Disease (AD) and Alzheimer’s related dementias affect millions of people every year, are a leading cause of death in the U.S, and have associated care costs estimated at US $818 billion globally [1,2]
Aβ42 abundance oscillates with a circadian period, microglia and macrophages have been shown to phagocytize Aβ42, and phagocytosis by macrophages is under circadian regulation, leading us to hypothesize that oscillations in the metabolism of Aβ42 may stem from the circadian regulation of phagocytosis in cells from myeloid lineages [12,14,28]
We modified a previously-employed BMDM phagocytosis assay, to use fluorescently labeled Aβ42 to determine if the phagocytosis of Aβ42 is controlled by the circadian clock [28,36,37,38]
Summary
Alzheimer’s Disease (AD) and Alzheimer’s related dementias affect millions of people every year, are a leading cause of death in the U.S, and have associated care costs estimated at US $818 billion globally [1,2]. Increasing neuroinflammation due to the accumulation of Aβ42 plaques leads to elevated levels of macrophage markers, activating microglia and increasing peripheral macrophage migration across the blood brain barrier (BBB), where peripheral macrophages more efficiently clear Aβ42 [7,11,12,13,14,15,16,17]. A double-edged sword, increased microglial activation and peripheral macrophage migration enhances the already high levels of neuroinflammation, leading to heightened cell death and exacerbating disease phenotypes [18,19,20,21,22,23,24,25]. The circadian clock exerts extensive influence over macrophage/microglial behavior and disruption of circadian regulation affects the ability of macrophages to phagocytize target particles [26,27,28] (S1 Fig). Despite the correlation between circadian Aβ42 abundance and circadian control of macrophage/microglial phagocytosis, the link between AD and the clock via the circadian timing of Aβ42 phagocytosis has not been examined
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