Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.
The major component of the cerebral plaques in Alzheimer disease is the beta-amyloid peptide, but serine proteinase inhibitors like alpha 1-antichymotrypsin (ACT) are also present. Their role in the pathogenesis of amyloid formation is unsettled. In addition to their function as proteinase inhibitors, serine proteinase inhibitors can interact with various hydrophobic compounds, a reaction accompanied by a transition from the stressed to the relaxed conformation. We report here on the ability of ACT to regulate the formation of beta-amyloid fibrils in vitro. In a molar ratio of 1:10 (ACT to beta-amyloid) ACT inhibits beta-amyloid fibril formation. Furthermore, ACT promotes rapid disaggregation of beta-amyloid fibrils when added in the same molar ratio to preformed beta-amyloid fibrils. These processes are accompanied by increased thermostability of ACT and loss of its biological activity, consistent with a conformational transition of ACT from the stressed to the relaxed state. The influence of ACT on beta-amyloid fibril formation may be an example of a hydrophobic interaction between the beta-amyloid peptide and the hydrophobic domain C terminal to the reactive center of ACT.
Eriksson
S
S
Department of Medicine, Lund University, Malmö General Hospital, Sweden.
Janciauskiene
S
S
Lannfelt
L
L
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000187:drug effects* / Q000648:ultrastructure*; D004355:Drug Stability; D004587:Electrophoresis, Agar Gel; D006801:Humans; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D013816:Thermodynamics; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D000514:alpha 1-Antichymotrypsin