ALPHA(2)-MACROGLOBULIN AS A BETA-AMYLOID PEPTIDE-BINDING PLASMA-PROTEIN

The beta-amyloid peptide (A beta) is a normal proteolytic processing p roduct of the amyloid precursor protein, which is constitutively expre ssed by many, if not most, cells. For reasons that are still unclear, A beta is deposited in an aggregated fibrillar form in both diffuse an d senile plaques in the brains of patients with Alzheimer's disease (A D). The factor(s) responsible for the clearance of soluble A beta from biological fluids or tissues are poorly understood. We now report tha t human alpha(2)-macroglobulin (alpha(2)M), a major circulating endopr oteinase inhibitor, which has recently been shown to be present in sen ile plaques in AD, binds I-125-A beta((1-42)) with high affinity (appa rent dissociation constant of 3.8 x 10(-10) M). Approximately 1 mol of A beta is bound per mole of alpha(2)M Both native and methylamine-act ivated alpha(2)M bind I-125-A beta((1-42)). The binding of I-125-A bet a((1-42)) to alpha(2)M is enhanced by micromolar concentrations of Zn2 + (but not Ca2+) and is inhibited by noniodinated A beta((1-42)) and A beta((1-40)) but not by the reverse peptide A beta((40-1)) or the cyt okines interleukin 1 beta or interleukin 2. alpha(1)-Antichymotrypsin, another plaque-associated; protein, inhibits both the binding of I-12 5-A beta((1-42)) to alpha(2)M as well as the degradation of I-125-A be ta((1-42)) by proteinase-activated alpha(2)M Moreover, the binding of I-125-A beta((1-42)) to alpha(2)M protects the peptide from proteolysi s by exogenous trypsin. These data suggest that alpha(2)M may function as a carrier protein for A beta and could serve to either facilitate or impede clearance of A beta from tissues such as the brain.