Functional border-associated macrophages limit Alzheimer’s Disease progression

Abstract Brain-resident macrophages are known to play numerous roles in the progression of Alzheimer’s Disease (AD). However, the relative contribution of microglia and border-associated macrophages (BAM) to AD pathogenesis has been difficult to disentangle. We recently identified Maf , a newly described AD GWAS gene, as essential for BAM, but not microglial, survival. By crossing BAM depleted mice with the 5xFAD AD model, we found stark evidence of cerebral amyloid angiopathy (CAA), increased overall β-amyloid burden, accelerated markers of neurodegeneration, and early memory deficits. In the healthy brain, BAM take up more β-amyloid per cell than microglia. However, as disease progresses, both in human AD patient samples and model AD mice, BAM number is reduced, and the remaining BAMs display impaired endocytic capacity, and show signs of metabolic exhaustion at an earlier age than microglia. Thus, strategies to preserve or restore BAM function represents a novel therapeutic avenue for AD and CAA.