TY - JOUR
T1 - The Formation Mechanism of Segmented Ring-Shaped Aβ Oligomers and Protofibrils
AU - Choi, Hyunsung
AU - Lee, Wonseok
AU - Lee, Gyudo
AU - Yoon, Dae Sung
AU - Na, Sungsoo
N1 - Funding Information:
Dae Sung Yoon gratefully acknowledges the Basic Science Research Program, through the National Research Foundation of Korea (NRF, Grant no. 2019R1A2B5B01070617, and NRF, Grant no. 2018M3C1B7020722).
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/8/21
Y1 - 2019/8/21
N2 - A clear understanding of amyloid formation with diverse morphologies is critical to overcoming the fatal disease amyloidosis. Studies have revealed that monomer concentration is a crucial factor for determining amyloid morphologies, such as protofibrils, annular, or spherical oligomers. However, gaining a complete understanding of the mechanism of formation of the various amyloid morphologies has been limited by the lack of experimental devices and insufficient knowledge. In this study, we demonstrate that the monomer concentration is an essential factor in determining the morphology of beta-amyloid (Aβ) oligomers or protofibrils. By computational and experimental approaches, we investigated the strategies for structural stabilization of amyloid protein, the morphological changes, and amyloid aggregation. In particular, we found unprecedented conformations, e.g., single bent oligomers and segmented ring-shaped protofibrils, the formation of which was explained by the computational analysis. Our findings provide insight into the structural features of amyloid molecules formed at low concentrations of monomer, which will help determine the clinical targets (in therapy) to effectively inhibit amyloid formation in the early stages of the amyloid growth phase.
AB - A clear understanding of amyloid formation with diverse morphologies is critical to overcoming the fatal disease amyloidosis. Studies have revealed that monomer concentration is a crucial factor for determining amyloid morphologies, such as protofibrils, annular, or spherical oligomers. However, gaining a complete understanding of the mechanism of formation of the various amyloid morphologies has been limited by the lack of experimental devices and insufficient knowledge. In this study, we demonstrate that the monomer concentration is an essential factor in determining the morphology of beta-amyloid (Aβ) oligomers or protofibrils. By computational and experimental approaches, we investigated the strategies for structural stabilization of amyloid protein, the morphological changes, and amyloid aggregation. In particular, we found unprecedented conformations, e.g., single bent oligomers and segmented ring-shaped protofibrils, the formation of which was explained by the computational analysis. Our findings provide insight into the structural features of amyloid molecules formed at low concentrations of monomer, which will help determine the clinical targets (in therapy) to effectively inhibit amyloid formation in the early stages of the amyloid growth phase.
KW - atomic force microscopy
KW - beta-amyloid
KW - molecular dynamics
KW - p3 peptide
KW - segmented ring-shaped structure
UR - http://www.scopus.com/inward/record.url?scp=85071708250&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.9b00324
DO - 10.1021/acschemneuro.9b00324
M3 - Article
C2 - 31313912
AN - SCOPUS:85071708250
SN - 1948-7193
VL - 10
SP - 3830
EP - 3838
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 8
ER -