Abstract
Alzheimer disease (AD) is a neurodegenerative disorder characterized by the aberrant production and accumulation of amyloid-β (Aβ) peptides in the brain. Accumulated Aβ in soluble oligomer and insoluble plaque forms are considered to be a pathological culprit and biomarker of the disorder. Here, we report a fluorescent universal Aβ-indicator YI-13, 5-(4-fluorobenzoyl)-7,8-dihydropyrrolo[1,2-b]isoquinolin-9(6H)-one, which detects Aβ monomers, dimers, and plaques. We synthesized a library of 26 fluorescence chemicals with the indolizine core and screen them through a series of in vitro tests utilizing Aβ as a target and YI-13 was selected as the final imaging candidate. YI-13 was found to stain and visualize insoluble Aβ plaques in the brain tissue, of a transgenic mouse model with five familial AD mutations (5XFAD), by a histochemical approach and to label soluble Aβ oligomers within brain lysates of the mouse model under a fluorescence plate reader. Among oligomers aggregated from monomers and synthetic dimers from chemically conjugated monomers, YI-13 preferred the dimeric Aβ.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / diagnosis*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides / chemistry*
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Amyloid beta-Peptides / metabolism*
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Animals
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Brain / metabolism*
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Disease Models, Animal
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Female
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Fluorescence
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Humans
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Indolizines / chemical synthesis*
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Indolizines / chemistry
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Indolizines / pharmacology*
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Mice
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Mice, Transgenic
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Molecular Structure
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Mutation
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Protein Multimerization
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
Substances
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Amyloid beta-Peptides
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Indolizines
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Small Molecule Libraries
Grants and funding
- Korea Health Industry Development Institute (HI18C0836)(URL:
https://www.khidi.or.kr) awarded to YK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. - National Research Foundation of Korea (Basic Science Research Program NRF-2018R1A6A1A03023718, Original Technology Research Program for Brain Science NRF-2018M3C7A1021858)(URL:
http://www.nrf.re.kr) awarded to YK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. - National Research Foundation of Korea (NRF-2020R1A2C2005961)(URL:
http://www.nrf.re.kr) awarded to IK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. - POSCO TJ Park Foundation (POSCO Science Fellowship)(URL:
https://www.postf.org) awarded to YK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. - The funder, BioActs, provided support in the form of salaries for author J. Park, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.