α₂‐Macroglobulin as a β‐Amyloid Peptide‐Binding Plasma Protein

Abstract

Abstract: The β‐amyloid peptide (Aβ) is a normal proteolytic processing product of the amyloid precursor protein, which is constitutively expressed by many, if not most, cells. For reasons that are still unclear, Aβ is deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease (AD). The factor(s) responsible for the clearance of soluble Aβ from biological fluids or tissues are poorly understood. We now report that human α 2 ‐macroglobulin (α 2 M), a major circulating endoproteinase inhibitor, which has recently been shown to be present in senile plaques in AD, binds 125 I‐Aβ (1–42) with high affinity (apparent dissociation constant of 3.8 × 10 −10 M ). Approximately 1 mol of Aβ is bound per mole of α 2 M. Both native and methylamine‐activated α 2 M bind 125 I‐Aβ (1–42) . The binding of 125 I‐Aβ (1–42) to α 2 M is enhanced by micromolar concentrations of Zn 2+ (but not Ca 2+ ) and is inhibited by noniodinated Aβ (1–42) and Aβ (1–40) but not by the reverse peptide Aβ (40‐1) or the cytokines interleukin 1β or interleukin 2. α 1 ‐Antichymotrypsin, another plaque‐associated protein, inhibits both the binding of 125 I‐Aβ (1–42) to α 2 M as well as the degradation of 125 I‐Aβ (1–42) by proteinase‐activated α 2 M. Moreover, the binding of 125 I‐Aβ (1–42) to α 2 M protects the peptide from proteolysis by exogenous trypsin. These data suggest that α 2 M may function as a carrier protein for Aβ and could serve to either facilitate or impede clearance of Aβ from tissues such as the brain.