Alpha 1-antichymotrypsin binding to Alzheimer A beta peptides is sequence specific and induces fibril disaggregation in vitro.

The serine protease inhibitor alpha 1-antichymotrypsin (ACT) consistently colocalizes with amyloid deposits of Alzheimer's disease (AD) and may contribute to the generation of amyloid proteins and/or physically affect fibril assembly. AD amyloid fibrils are composed primarily of A beta, which is a proteolytic fragment of the larger beta-amyloid precursor protein. Using negative-stain and immunochemical electron microscopy, we have investigated the binding of ACT to the fibrils formed by four synthetic A beta analogues corresponding to the wild-type human 1-40 sequence [Hwt(1-40)], a 1-40 peptide [HDu(1-40)] containing the Glu22-->Gln mutation found in hereditary cerebral hemorrhage with amyloidosis of the Dutch type, the N-terminal 1-28 residues [beta(1-28)], and an internal fragment of A beta containing residues 11-28 [beta(11-28)]. Each of these peptide analogues assembled into 70-90-A-diameter fibrils resembling native amyloid and, except for beta(11-28), bound ACT, as indicated by the appearance of 80-100-A globular particles that adhered to preformed fibrils and that could be decorated with anti-ACT antibodies. Under the conditions used, ACT binding destabilized the in vitro fibrils and produced a gradual dissolution of the macromolecular assemblies into constituent filaments and shorter fragments. The internal fragment (11-28) did not exhibit ACT binding or any structural changes. These results suggest that a specific sequence likely contained within the N-terminal 10 residues of A beta is responsible for the formation of the ACT-amyloid complex.(ABSTRACT TRUNCATED AT 250 WORDS)