Structural progression of amyloid-β Arctic mutant aggregation in cells revealed by multiparametric imaging. ...

• Main Authors: Lu, Meng, Williamson, Neil, Mishra, Ajay, Michel, Claire H, Kaminski, Clemens F, Tunnacliffe, Alan, Kaminski Schierle, Gabriele S
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier BV 2019
• Subjects: 3D structure of amyloid aggregates; Alzheimer's disease; Arctic mutant; SIM; amyloid-β; amyloid-β Aβ; microscopic imaging; molecular dynamics; neurodegeneration; protein aggregation; structural model; Amyloid beta-Peptides; Humans; Kinetics; Microscopy, Confocal; Microscopy, Fluorescence; Models, Molecular; Mutation; Optical Imaging; Protein Conformation; Protein Multimerization; Arctic
• Online Access: https://dx.doi.org/10.17863/cam.39973; https://www.repository.cam.ac.uk/handle/1810/292817

The 42-amino-acid β-amyloid (Aβ42) is a critical causative agent in the pathology of Alzheimer's disease. The hereditary Arctic mutation of Aβ42 (E22G) leads to increased intracellular accumulation of β-amyloid in early-onset Alzheimer's disease. However, it remains largely unknown how the Arctic mutant variant leads to aggressive protein aggregation and increased intracellular toxicity. Here, we constructed stable cell lines expressing fluorescent-tagged wildtype (WT) and E22G Aβ42 to study the aggregation kinetics of the Arctic Aβ42 mutant peptide and its heterogeneous structural forms. Arctic-mutant peptides assemble and form fibrils at a much faster rate than WT peptides. We identified five categories of intracellular aggregate-oligomers, single fibrils, fibril bundles, clusters, and aggresomes-that underline the heterogeneity of these Aβ42 aggregates and represent the progression of Aβ42 aggregation within the cell. Fluorescence-lifetime imaging (FLIM) and 3D structural illumination microscopy (SIM) ...