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FLIM Imaging Reveals a Toxicogenic Interaction between Amyloid-? and Apolipoprotein-E
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788208
*Corresponding author: (e-mail: maiti@tifr.res.in).
Abstract
Background: The apolipoprotein E-4 (ApoE) isoform is a major genetic risk factor associated with Alzheimer’s disease (AD). However, a detailed molecular-level understanding of ApoE’s involvement in AD pathology remains elusive.
Materials and Methods: In this work, we utilized fluorescence lifetime imaging to observe reporter fluorescent Aβ oligomers across various ApoE-containing cells, along with advanced single-molecule fluorescence characterizations such as single-molecule photobleaching (smPB) and two-dimensional fluorescence lifetime correlation spectroscopy (2D-FLCS) to address the effect of ApoE on Aβ oligomers.
Results: Investigating ApoE-dependent alterations of Aβ, we observed the emergence of a new species of Aβ oligomer with a distinct lifetime, which varied across cell types, correlating with ApoE concentrations. smPB and 2D-FLCS of these modified Aβ oligomers, extracted from cells, revealed that the lifetime-modified Aβ oligomers were rich in dimers and had an elevated affinity for lipid bilayers. Fluorescence quenching indicated a conformational change in these cell-extracted oligomers. The addition of an Aβ–ApoE interaction inhibitor, LVFFA, reduced both lifetime modification and oligomer toxicity in a dose-responsive manner, revealing a direct role of ApoE-induced Aβ in AD.
Conclusion: Our data provide insights into a previously unknown toxic transformation of intracellular Aβ oligomers induced by ApoE. Additionally, understanding the origin of the fluorescence lifetime change in reporter Aβ paves the way for novel AD drug discovery platforms.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: maiti@tifr.res.in).
Abstract
Background: The apolipoprotein E-4 (ApoE) isoform is a major genetic risk factor associated with Alzheimer’s disease (AD). However, a detailed molecular-level understanding of ApoE’s involvement in AD pathology remains elusive.
Materials and Methods: In this work, we utilized fluorescence lifetime imaging to observe reporter fluorescent Aβ oligomers across various ApoE-containing cells, along with advanced single-molecule fluorescence characterizations such as single-molecule photobleaching (smPB) and two-dimensional fluorescence lifetime correlation spectroscopy (2D-FLCS) to address the effect of ApoE on Aβ oligomers.
Results: Investigating ApoE-dependent alterations of Aβ, we observed the emergence of a new species of Aβ oligomer with a distinct lifetime, which varied across cell types, correlating with ApoE concentrations. smPB and 2D-FLCS of these modified Aβ oligomers, extracted from cells, revealed that the lifetime-modified Aβ oligomers were rich in dimers and had an elevated affinity for lipid bilayers. Fluorescence quenching indicated a conformational change in these cell-extracted oligomers. The addition of an Aβ–ApoE interaction inhibitor, LVFFA, reduced both lifetime modification and oligomer toxicity in a dose-responsive manner, revealing a direct role of ApoE-induced Aβ in AD.
Conclusion: Our data provide insights into a previously unknown toxic transformation of intracellular Aβ oligomers induced by ApoE. Additionally, understanding the origin of the fluorescence lifetime change in reporter Aβ paves the way for novel AD drug discovery platforms.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India