Microglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis

Alzheimer's disease is characterized by the progressive deposition of beta-amyloid (A beta) within the brain parenchyma and its subsequent accumulation into senile plaques. Pathogenesis of the disease is associated with perturbations in A beta homeostasis and the inefficient clearance of these soluble and insoluble peptides from the brain. Microglia have been reported to mediate the clearance of fibrillar A beta (fA beta) through receptor-mediated phagocytosis; however, their participation in clearance of soluble A beta peptides (sA beta) is largely unknown. We report that microglia internalize sA beta from the extracellular milieu through a nonsaturable, fluid phase macropinocytic mechanism that is distinct from phagocytosis and receptor-mediated endocytosis both in vitro and in vivo. The uptake of sA beta is dependent on both actin and tubulin dynamics and does not involve clathrin assembly, coated vesicles or membrane cholesterol. Upon internalization, fluorescently labeled sA beta colocalizes to pinocytic vesicles. Microglia rapidly traffic these soluble peptides into late endolysosomal compartments where they are subject to degradation. Additionally, we demonstrate that the uptake of sA beta and fA beta occurs largely through distinct mechanisms and upon internalization are segregated into separate subcellular vesicular compartments. Significantly, we found that upon proteolytic degradation of fluorescently labeled sA beta, the fluorescent chromophore is retained by the microglial cell. These studies identify an important mechanism through which microglial cells participate in the maintenance of A beta homeostasis, through their capacity to constitutively clear sA beta peptides from the brain.