title: Nucleation-dependent polymerization is an essential component of amyloid-mediated neuronal cell death.
abstract: Accumulating evidence suggests that amyloid protein aggregation is pathogenic in many diseases, including Alzheimer's disease. However, the mechanisms by which protein aggregation mediates cellular dysfunction and overt cell death are unknown. Recent reports have focused on the potential role of amyloid oligomers or protofibrils as a neurotoxic form of amyloid-beta (Abeta) and related amyloid aggregates. Here we describe studies indicating that overt neuronal cell death mediated by Abeta(1-40) is critically dependent on ongoing Abeta(1-40) polymerization and is not mediated by a single stable species of neurotoxic aggregate. The extent and rate of neuronal cell death can be controlled by conditions that alter the rate of Abeta polymerization. The results presented here indicate that protofibrils and oligomeric forms of Abeta most likely generate neuronal cell death through a nucleation-dependent process rather than acting as direct neurotoxic ligands. These findings bring into question the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide formazan assay (MTT assay) as a reporter of Abeta-mediated neuronal cell death and suggest that diffusible Abeta protofibrils and oligomers more likely mediate subtle alterations of synaptic function and long-term potentiation rather than overt neuronal cell death. These results have been extended to Abeta(1-42), the non-Abeta component of Alzheimer's disease amyloid plaques, and human amylin, suggesting that nucleation-dependent polymerization is a common mechanism of amyloid-mediated neuronal cell death. Our findings indicate that ongoing amyloid fibrillogenesis may be an essential mechanistic process underlying the pathogenesis associated with protein aggregation in amyloid disorders.
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wogulis
authors.forename: Sarah
authors.initials: S
authors.lastname: Wright
authors.forename: Damian
authors.initials: D
authors.lastname: Cunningham
authors.forename: Tamie
authors.initials: T
authors.lastname: Chilcote
authors.forename: Kyle
authors.initials: K
authors.lastname: Powell
authors.forename: Russell E
authors.initials: RE
authors.lastname: Rydel
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D016477:Artifacts; D001704:Biopolymers; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D004396:Coloring Agents / Q000032:analysis / Q000737:chemistry; D003460:Crystallization; D005562:Formazans / Q000032:analysis / Q000737:chemistry; D006801:Humans; D058228:Islet Amyloid Polypeptide; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008956:Models, Chemical; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D012995:Solubility; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000032:analysis / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D001704:Biopolymers; D004396:Coloring Agents; D005562:Formazans; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C079782:MTT formazan; C022616:thiazolyl blue