The role of brain border-associated macrophages in aging and cerebral amyloid angiopathy

Abstract The health of the brain vasculature is essential for Cerebral amyloid angiopathy (CAA) results from the deposition of amyloid proteins onto blood vessels, and is observed in a very high percentage of patients with Alzheimer’s disease (AD), as well as in AD animal models. It has been proposed that central nervous system (CNS) macrophages are important in keeping the brain clean of toxic depositions. Microglia are the most abundant macrophages in the CNS. There are also non-microglial macrophages, which in this application are called Border-Associated macrophages (BAM). Our central hypothesis is that microglia, due to its parenchymal location, keeps clean the brain from unused neural connection, while BAM, which have a perivascular location, exert similar functions but targeting the vasculature. The dominant population (70-80%) of BAM in young adult mice is comprised of cells that express high levels of CD206, Lyve1, CD38 and Tim4, and low levels of MHC class II molecules (CD206HI MHC IILO). Imaging studies show that these cells are tightly associated with the blood vasculature, displaying a high capacity to endocytose macromolecules injected into the blood circulation. Our data show that BAMs’ endocytic capacity is impaired in aged mice as well as mice with CAA. It is, however, difficult to study the role of BAMs without the availability of specific reagents. We have developed three mouse strains, Lyve1-Cre X Maf f/f, LysM-Cre Maf f/f, and Csf1r-Cre Maf f/f that lacks CD206HI MHC IILO BAMs but have an intact microglial compartment. This is the first genetic tool that can be used to specifically target perivascular macrophages in the brain. CD206HI BAM-deficient mice have expanded brain vasculature in your mice, and exaggerated amyloid deposition in a mouse model of CAA. We therefore believe that BAM are important to maintain the vasculature, and that our genetic tool will be useful in clarifying BAM’s function.