title: Interaction between A beta(1-42) and A beta(1-40) in Alzheimer's beta-amyloid fibril formation in vitro.
abstract: We analyzed the interaction of two kinds of amyloid beta-peptides (A beta), i.e., A beta(1-42) and A beta(1-40), in the kinetics of beta-amyloid fibril (fA beta) formation in vitro, based on a nucleation-dependent polymerization model using fluorescence spectroscopy with thioflavin T. When 25 microM A beta(1-42) was incubated with increasing concentrations of amyloidogenic A beta(1-40), the time to proceed to equilibrium was extended dose-dependently. A similar inhibitory effect was observed when 45 microM A beta(1-40) was incubated with increasing concentrations of A beta(1-42). On the other hand, when 50 microM of nonamyloidogenic A beta(1-40) was incubated with A beta(1-42) at a molar ratio of 10:1 or 5:1, A beta(1-42) initiated fA beta formation from A beta(1-40). The lag time of the reaction shortened in a concentration-dependent manner, with A beta(1-42). We next examined the seeding effect of fA beta formed from A beta(1-42) (fA beta(1-42)) on nonamyloidogenic A beta(1-40). When 50 microM of nonamyloidogenic A beta(1-40) was incubated with 10 or 20 microg/mL (2.2 or 4.4 microM) of fA beta(1-42), the fluorescence showed a sigmoidal increase. The lag time of the reaction was shortened by fA beta(1-42) in a concentration-dependent manner. However, the time to proceed to equilibrium was much longer than when an equal concentration of fA beta formed from A beta(1-40) (fA beta(1-40)) was added to A beta(1-40). The fluorescence increased hyperbolically without a lag phase when 25 microM A beta(1-42) was incubated with 10 or 20 microg/mL (2.3 or 4.6 microM) of fA beta(1-40), and proceeded to equilibrium more rapidly than without fA beta(1-40). An electron microscopic study indicated that the morphology of fA beta formed is governed by the major component of fresh A beta peptides in the reaction mixture, not by the morphology of preexisting fibrils. These results may indicate the central role of A beta(1-42) for fA beta deposition in vivo, among the different coexisting A beta species.
authors.affiliation: Department of Pathology, Fukui Medical University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hasegawa
authors.forename: I
authors.initials: I
authors.lastname: Yamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Omata
authors.forename: F
authors.initials: F
authors.lastname: Gejyo
authors.forename: H
authors.initials: H
authors.lastname: Naiki
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D008954:Models, Biological; D008956:Models, Chemical; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D013050:Spectrometry, Fluorescence
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)