Brain border-associated macrophages rhythmically scavenge amyloid-beta and regulate vascular amyloid pathology

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. We find that the rest phase is a specialized time for BAM engulfment, characterized by upregulation of endocytic machinery 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, deletion of Bmal1 in BAMs worsens perivascular and leptomeningeal Aβ plaque burden. Our results characterize rapid endocytosis of fluid-borne substrates as a specialized and rhythmic BAM function and identify perturbed timing of brain border immune function as one potential avenue by which circadian disruptions may precipitate amyloidosis.