Investigating the circadian control of macrophage phagocytosis and physiology and its impact on alzheimer’s disease risk and progression

Abstract

The circadian rhythm is a molecular oscillator that regulates the sleep/wake cycle and governs various processes, including immune functions such as cytokine expression, phagocytosis, and immune cell migration to inflamed tissues. This results in a pro-inflammatory state during the organism's active phase and an anti-inflammatory state during the organism's inactive phase. Circadian disruption (CD) increases disease risks and plays a bidirectional role in the risk and pathogenesis of Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, with sleep disturbances starting years before disease onset and worsening as the disease progresses. Additionally, inflammation, primarily driven by the innate immune system, plays a vital role in AD pathogenesis, as patients with AD have increased neuroinflammation and systemic inflammation. This study examines the role of bone marrow-derived macrophages (BMDMs) in AD and demonstrates the circadian oscillation of Aβ42 phagocytosis, which is mediated by the circadian expression of cell surface heparan sulfate proteoglycans (HSPGs). This oscillation governs macrophage response to Aβ42 based on the time of day of exposure, with mitogen-activated protein kinase (MAPK) signaling triggered by Aβ42 during the inactive phase and tumor necrosis factor (TNF) signaling triggered by Aβ42 during the active phase. Additionally, this work demonstrates inherent changes to macrophage circadian protein expression, phagocytosis of Aβ42, and intracellular reactive oxygen species (ROS) generation in both AD and CD, with CD models demonstrating AD-like phenotypes. These inherent changes to BMDMs were observed prior to cognitive decline in AD models, therefore suggesting that circadian immune functions are critical in preventing inflammation and AD. In total, this work provides new insights into the intricate interplay between circadian rhythms, the innate immune system, and AD.