The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophages

SUMMARY Circadian disruptions perturb the brain and immune system and increase the risk of developing Alzheimer’s Disease (AD), yet whether this involves dysregulation of brain immunity remains less clear. Here, we perform single-cell RNA sequencing of the brain immune compartment around the day-night cycle and identify brain border-associated macrophages (BAMs) as highly rhythmic cells. During the rest phase, we find that BAMs exhibit coordinated upregulation of endocytic genes and enhanced uptake of extracellular fluid-borne material including amyloid-beta (Aβ). Rhythmicity in BAM scavenging is regulated by the clock gene Bmal1 , mediated by the endocytic receptor CD206, and perturbed with age. In a mouse model of AD, we show that deletion of Bmal1 in BAMs worsens perivascular and leptomeningeal Aβ plaque burden. Our results identify endocytosis as a specialized and rhythmic BAM function and identify perturbed timing of brain border immune functions as a potential mechanism by which circadian disruptions precipitate amyloidosis.