Abstract : Apolipoprotein E and α2-macroglobulin (α2M) are genetic risk factors for late-onset Alzheimer's disease, and both bind a cell surface receptor, the lowdensity lipoprotein receptor-related protein (LRP). To investigate the role of LRP on preventing the accumulation of β-amyloid peptide (Aβ), we examined the effects of α2M on the clearance of endogenous Aβ. Studies were performed in primary Tg2576 transgenic mouse cortical neuronal cultures expressing human mutant amyloid precursor protein (APP) 695. This system allowed us to follow endogenous Aβ using immunoblots to detect monomeric forms of the peptide. Aβ and APP levels were measured in conditioned media. We found that activated α2M (α2M*) substantially decreased soluble Aβ levels and had no effect on secreted or full-length APP levels. Native α2M, which is not a ligand for LRP, did not affect Aβ levels. The receptor-associated protein, which inhibits interaction of all ligands with LRP in vitro, prevented α2M*-induced decreases of soluble Aβ levels. These data suggest that α2M* affects soluble Aβ clearance rather than Aβ production. Further studies showed that similar Aβ clearance via an LRP-mediated pathway was observed after treatment with another LRP ligand, lactoferrin. Taken together, these data demonstrate that α2M* enhances the clearance of soluble Aβ via LRP in cortical neurons.