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Heterogeneous aggregation of amyloid-β 42 from single-molecule spectroscopy

Fanjie Meng, Janghyun Yoo, View ORCID ProfileHoi Sung Chung
doi: https://doi.org/10.1101/2020.09.10.290023
Fanjie Meng
1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0520
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Janghyun Yoo
1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0520
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Hoi Sung Chung
1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0520
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  • ORCID record for Hoi Sung Chung
  • For correspondence: chunghoi@niddk.nih.gov
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Abstract

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 Statement

The authors have declared no competing interest.

Footnotes

  • ↵* email: fanjie.meng{at}nih.gov (F.M.); janghyun.yoo{at}nih.gov (J.Y.); chunghoi{at}niddk.nih.gov (H.S.C.)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted September 11, 2020.
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Heterogeneous aggregation of amyloid-β 42 from single-molecule spectroscopy
Fanjie Meng, Janghyun Yoo, Hoi Sung Chung
bioRxiv 2020.09.10.290023; doi: https://doi.org/10.1101/2020.09.10.290023
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Heterogeneous aggregation of amyloid-β 42 from single-molecule spectroscopy
Fanjie Meng, Janghyun Yoo, Hoi Sung Chung
bioRxiv 2020.09.10.290023; doi: https://doi.org/10.1101/2020.09.10.290023

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