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Alzheimer's disease is characterized by the progressive deposition of beta-amyloid (Abeta) within the brain parenchyma and its subsequent accumulation into senile plaques. Pathogenesis of the disease is associated with perturbations in Abeta homeostasis and the inefficient clearance of these soluble and insoluble peptides from the brain. Microglia have been reported to mediate the clearance of fibrillar Abeta (fAbeta) through receptor-mediated phagocytosis; however, their participation in clearance of soluble Abeta peptides (sAbeta) is largely unknown. We report that microglia internalize sAbeta 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 sAbeta is dependent on both actin and tubulin dynamics and does not involve clathrin assembly, coated vesicles or membrane cholesterol. Upon internalization, fluorescently labeled sAbeta 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 sAbeta and fAbeta 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 sAbeta, the fluorescent chromophore is retained by the microglial cell. These studies identify an important mechanism through which microglial cells participate in the maintenance of Abeta homeostasis, through their capacity to constitutively clear sAbeta peptides from the brain.

Microglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis