title: Alzheimer peptides aggregate into transient nanoglobules that nucleate fibrils.
abstract: Protein/peptide oligomerization, cross-β strand fibrillation, and amyloid deposition play a critical role in many diseases, but despite extensive biophysical characterization, the structural and dynamic details of oligomerization and fibrillation of amyloidic peptides/proteins remain to be fully clarified. Here, we simultaneously monitored the atomic, molecular, and mesoscopic states of aggregating Alzheimer's amyloid β (Aβ) peptides over time, using a slow aggregation protocol and a fast aggregation protocol, and determined the cytotoxicity of the intermediate states. We show that in the early stage of fast fibrillation (the lag phase) the Aβ peptides coalesced into apparently unstructured globules (15-200 nm in diameter), which slowly grew larger. Then a sharp transition occurred, characterized by the first appearance of single fibrillar structures of approximately ≥100 nm. These fibrils emerged from the globules. Simultaneously, an increase was observed for the cross-β strand conformation that is characteristic of the fibrils that constitute mature amyloid. The number and size of single fibrils rapidly increased. Eventually, the fibrils coalesced into mature amyloid. Samples from the early lag phase of slow fibrillation conditions were especially toxic to cells, and this toxicity sharply decreased when fibrils formed and matured into amyloid. Our results suggest that the formation of fibrils may protect cells by reducing the toxic structures that appear in the early lag phase of fibrillation.
authors.affiliation: Leiden Institute of Chemistry, Leiden University , Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Luo
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.forename: Jan Pieter
authors.initials: JP
authors.lastname: Abrahams
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000737:chemistry / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D049329:Nanostructures; D010446:Peptide Fragments / Q000737:chemistry* / Q000502:physiology; D066263:Protein Aggregation, Pathological
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)