Brain macrophages in Alzheimer's disease: from ontogeny to function

Abstract

In the Alzheimer’s disease (AD) brain, microglia and border-associated macrophages (BAMs) undergo dynamic identity changes and display distinct activation and functional (or dysfunctional) states, which remains to be fully elucidated. Using an APP-KI AD mouse model, we demonstrated that microglia and activated CD11c+ microglia were monocyte-independent and maintained their yolk-sac origin by self-renewal. At the brain borders, the embryonic-derived BAMs were minimally replaced by bone marrow (BM)-derived cells in adulthood, except for dura mater (DM) macrophages, whose niche allowed monocyte replenishment. Concerning functional states, we identified a propensity of macrophages to accumulate lipid droplets (LD) in the AD brain, which inversely correlates with their phagocytic activity. Using an inducible transgenic mouse model, we successfully reduced the lipid load in CX3CR1+ microglia and BAMs, which enhanced their phagocytic and efferocytic capabilities. This functional rewiring of brain macrophages resulted in a significant reduction of Aβ deposition in AD mouse brains. Therefore, targeting the lipid accumulation in microglia could potentially be exploited as a therapeutic strategy for treating AD.