RT Journal Article
SR Electronic
T1 Heterogeneous aggregation of amyloid-β 42 from single-molecule spectroscopy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.10.290023
DO 10.1101/2020.09.10.290023
A1 Fanjie Meng
A1 Janghyun Yoo
A1 Hoi Sung Chung
YR 2020
UL http://biorxiv.org/content/early/2020/09/11/2020.09.10.290023.abstract
AB Protein aggregation is implicated as the cause of pathology in various diseases such as Alzheimer’s and Parkinson’s disease. Polymorphism in the structure of fibrils formed by aggregation suggests the existence of many different assembly pathways and therefore a heterogeneous ensemble of soluble oligomers. Characterization of this heterogeneity is the key to understanding the aggregation mechanism and toxicity of specific oligomers, but in practice it is extremely difficult because oligomers cannot be readily separated. Here, we investigate highly heterogeneous oligomerization and fibril formation of the 42-residue amyloid-β peptide (Aβ42). We developed and used new single-molecule fluorescence spectroscopic and fluorescence lifetime imaging methods, combined with deep learning for image analysis. We found that the concentration of oligomers, including dimers, is extremely low and that the dimer is conformationally diverse. Aggregation to form fibrils is also highly heterogeneous in terms of the number of strands in a fibril and the elongation speed and conformation of fibrils. This heterogeneity in all stages of aggregation explains diverse and sometimes irreproducible results of experimental studies of amyloid-β. Based on our observations and analysis, we propose a new model for aggregation of Aβ42.Competing Interest StatementThe authors have declared no competing interest.