Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model

Macrophages accumulate lipid droplets (LD) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer’s disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. In particular, activated CD11c+ microglia, localized proximal to beta-amyloid (Aβ) plaques, had a pronounced lipid-associated gene signature and a higher LD load than other microglial subtypes. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1+ brain macrophages using an inducible transgenic mouse model. Reducing the lipid load of microglia and CX3CR1+ BAMs improved phagocytic and efferocytic capacities and significantly reduced Aβ deposition in the brain. Therefore, mitigating LD accumulation in microglia and BAMs provides new perspectives for the treatment of AD.