Alzheimer's peptide Aβ1-42 binds to two β-sheets of α1-antichymotrypsin and transforms it from inhibitor to substrate

The serpin alpha(1)-antichymotrypsin is a major component of brain amyloid plaques in Alzheimer's disease. In vitro alpha(1)-antichymotrypsin interacts with the Alzheimer's amyloid peptide A beta(1-42) and stimulates both formation and disruption of neurotoxic A beta(1-42) fibrils in a concentration-dependent manner. We have constructed a new hybrid model of the complex between A beta(1-42) and alpha(1)-antichymotrypsin in which both amino and carboxyl sequences of A beta(1-42) insert into two different beta-sheets of alpha(1)-antichymotrypsin. We have tested this model and shown experimentally that full-length and amino-terminal segments of A beta(1-42) bind to alpha(1)-antichymotrypsin as predicted. We also show that A beta(1-42) forms both intra- and intermolecular SDS-stable complexes with alpha(1)-antichymotrypsin and that the binding of A beta(1-42) to alpha(1)-antichymotrypsin abolishes the inhibitory activity of the latter and its ability to form stable complex with chymotrypsin. The existence of both inter- as well as intramolecular complexes of A beta(1-42) explains the nonlinear concentration-dependent effects of alpha(1)-antichymotrypsin on A beta(1-42) fibril formation, which we have reinvestigated here over a broad range of A beta(1-42):alpha(1)-antichymotrypsin ratios. These data suggest a molecular basis for the distinction between amorphous and fibrillar A beta(1-42) in vivo. The reciprocal effects of A beta(1-42) and alpha(1)-antichymotrypsin could play a role in the etiology of Alzheimer's disease.