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)
Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada.
P E
PE
Fraser
J T
JT
Nguyen
D R
DR
McLachlan
C R
CR
Abraham
D A
DA
Kirschner
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009454:Neurofibrils / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D000514:alpha 1-Antichymotrypsin / Q000378:metabolism*
D000682:Amyloid; D009479:Neuropeptides; D000514:alpha 1-Antichymotrypsin