ALPHA(2)-MACROGLOBULIN COMPLEXES WITH AND MEDIATES THE ENDOCYTOSIS OFBETA-AMYLOID PEPTIDE VIA CELL-SURFACE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN

A primary histopathological feature of Alzheimer's disease is the accu mulation of beta-amyloid (A beta) in the brain of afflicted individual s. However, A beta is produced continuously as a soluble protein in he althy individuals where it is detected in serum and CSF, suggesting th e existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that A beta forms stable complexes with activated alpha(2)-macroglobulin (alpha(2)M), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS, These alpha(2) M/I-125-A beta complexes are immunoreactive with both anti-A beta and anti-alpha(2)M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that al pha(2)M/I-125-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 interactio ns with LRP. In contrast, the degradation of free I-125-A beta is not inhibited by RAP and thus must be mediated via an LRP-independent path way. These results suggest that LRP can function as a clearance recept or for A beta via a physiological ligand.