Circadian disruption induces sex-specific Alzheimer’s pathophysiology and immune cell reprogramming

Summary Circadian disruption (CD) is increasingly recognized as a sex-specific risk factor for Alzheimer’s disease (AD). However, the mechanisms linking CD to AD, and the role of biological sex in this interaction, are unclear. Immunometabolic regulation is extensively circadianly timed, has sex-specific phenotypes, and plays a role in AD. Therefore, we hypothesized that CD affects the timing of immunometabolism, contributing to the sex-specific effects of CD on AD. To demonstrate this, we subjected male and female APP/PS1 mice to chronic disruptive lighting to model circadian disruption, finding CD induced a female-specific reduction in amyloid plaque burden but an increase in the infiltration of peripheral macrophages into the brain. Concomitantly, we found macrophages exhibited CD-associated immune reprogramming, which in females led to altered immunometabolic timing, an increase of macrophages in the activated state, and elevated levels of reactive oxygen species (ROS), supporting a role for immunometabolism in the sex-specific effects of CD in AD. Graphical Abstract Highlights Circadian disruption reduces Aβ plaque load specifically in female mice Peripheral immune infiltration correlates with reduced Aβ plaques in females Circadian disruption coordinates phasing of circadian immunometabolic proteins In females, circadian phase advancement correlates with increased ROS