α2-macroglobulin enhances the clearance of endogenous soluble β-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons

Apolipoprotein E and alpha(2)-macroglobulin (alpha 2M) are genetic risk factors for late-onset Alzheimer's disease, and both bind a cell surface receptor, the low-density lipoprotein receptor-related protein (LRP). To investigate the role of LRP on preventing the accumulation of beta-amyloid peptide (A beta), we examined the effects of alpha 2M on the clearance of endogenous A beta. 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 A beta using immunoblots to detect monomeric forms of the peptide. A beta and APP levels were measured in conditioned media. We found that activated alpha 2M (alpha 2M*) substantially decreased soluble A beta levels and had no effect on secreted or full-length APP levels. Native alpha 2M, which is not a ligand for LRP, did not affect A beta levels. The receptor-associated protein, which inhibits interaction of all ligands with LRP in vitro, prevented alpha 2M*-induced decreases of soluble A beta levels. These data suggest that alpha 2M* affects soluble A beta clearance rather than A beta production. Further studies showed that similar A beta clearance via an LRP-mediated pathway was observed after treatment with another LRP ligand, lactoferrin. Taken together, these data demonstrate that alpha 2M* enhances the clearance of soluble A beta via LRP in cortical neurons.