Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein

A primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid (A beta) in the brain of afflicted individuals. However, A beta is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that A beta forms stable complexes with activated alpha2-macroglobulin (alpha2M*), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS. These alpha2M*/125I-A beta complexes are immunoreactive with both anti-A beta and anti-alpha2M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that alpha2M*/125I-A beta complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor-associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125I-A beta is not inhibited by RAP and thus must be mediated via an LRP-independent pathway. These results suggest that LRP can function as a clearance receptor for A beta via a physiological ligand.