title: Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation.
abstract: The formation of amyloid β (Aβ) fibrils is crucial in initiating the cascade of pathological events that culminates in Alzheimer's disease. In this study, we investigated the mechanism of Aβ fibril formation from hydrodynamically well defined species under controlled aggregation conditions. We present a detailed mechanistic model that furnishes a novel insight into the process of Aβ42 fibril formation and the molecular basis for the different structural transitions in the amyloid pathway. Our data reveal the structure and polymorphism of Aβ fibrils to be critically influenced by the oligomeric state of the starting materials, the ratio of monomeric-to-aggregated forms of Aβ42 (oligomers and protofibrils), and the occurrence of secondary nucleation. We demonstrate that monomeric Aβ42 plays an important role in mediating structural transitions in the amyloid pathway, and for the first time, we provide evidences that Aβ42 fibrillization occurs via a combined mechanism of nucleated polymerization and secondary nucleation. These findings will have significant implications to our understanding of the molecular basis of amyloid formation in vivo, of the heterogeneity of Aβ pathology (e.g., diffuse versus amyloid plaques), and of the structural basis of Aβ toxicity.
authors: Laboratory of Physics of Living Matter, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. jaesun.jeong@epfl.ch
authors: Jae Sun
authors: JS
authors: Jeong
authors: Annalisa
authors: A
authors: Ansaloni
authors: Raffaele
authors: R
authors: Mezzenga
authors: Hilal A
authors: HA
authors: Lashuel
authors: Giovanni
authors: G
authors: Dietler
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D058225:Plaque, Amyloid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D058105:Polymerization; D011110:Polymorphism, Genetic; D055503:Protein Multimerization / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)