title: Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation.
abstract: The process of amyloid formation by the amyloid beta peptide (Abeta), i.e., the misassembly of Abetapeptides into soluble quaternary structures and, ultimately, amyloid fibrils, appears to be at the center of Alzheimer's disease (AD) pathology. We have shown that abnormal oxidative metabolites, including cholesterol-derived aldehydes, modify Abeta and accelerate the early stages of amyloidogenesis (the formation of spherical aggregates). This process, which we have termed metabolite-initiated protein misfolding, could explain why hypercholesterolemia and inflammation are risk factors for sporadic AD. Herein, the mechanism by which cholesterol metabolites hasten Abeta 1-40 amyloidogenesis is explored, revealing a process that has at least two steps. In the first step, metabolites modify Abeta peptides by Schiff base formation. The Abeta-metabolite adducts form spherical aggregates by a downhill polymerization that does not require a nucleation step, dramatically accelerating Abeta aggregation. In agitated samples, a second step occurs in which fibrillar aggregates form, a step also accelerated by cholesterol metabolites. However, the metabolites do not affect the rate of fibril growth in seeded aggregation assays; their role appears to be in initiating amyloidogenesis by lowering the critical concentration for aggregation into the nanomolar range. Small molecules that block Schiff base formation inhibit the metabolite effect, demonstrating the importance of the covalent adduct. Metabolite-initiated amyloidogenesis offers an explanation for how Abeta aggregation could occur at physiological nanomolar concentrations.
authors.affiliation: The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Bieschke
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D002942:Circular Dichroism; D006801:Humans; D066298:In Vitro Techniques; D018625:Microscopy, Atomic Force; D046912:Multiprotein Complexes; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D012545:Schiff Bases / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012545:Schiff Bases; C078592:amyloid beta-protein (1-40)