Tailoring Hydrophobic Interactions between Probes and Amyloid-β Peptides for Fluorescent Monitoring of Amyloid-β Aggregation

Sonam Kim, Hyuck Jin Lee, Eunju Nam, Donghyun Jeong, Jaeheung Cho, Mi Hee Lim, Youngmin You

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7 Scopus citations


Despite their unique advantages, the full potential of molecular probes for fluorescent monitoring of amyloid-β (Aβ) aggregates has not been fully exploited. This limited utility stems from the lack of knowledge about the hydrophobic interactions between the molecules of Aβ probes, as well as those between the probe and the Aβ aggregate. Herein, we report the first mechanistic study, which firmly establishes a structure-signaling relationship of fluorescent Aβ probes. We synthesized a series of five fluorescent Aβ probes based on an archetypal donor-acceptor-donor scaffold (denoted as SN1-SN5). The arylamino donor moieties were systematically varied to identify molecular factors that could influence the interactions between molecules of each probe and that could influence their fluorescence outcomes in conditions mimicking the biological milieu. Our probes displayed different responses to aggregates of Aβ, Aβ40 and Aβ42, two major isoforms found in Alzheimer's disease: SN2, having pyrrolidine donors, showed noticeable ratiometric fluorescence responses (Δ ν = 797 cm-1) to the Aβ40 and Aβ42 samples that contained oligomeric species, whereas SN4, having N-methylpiperazine donors, produced significant fluorescence turn-on signaling in response to Aβ aggregates, including oligomers, protofibrils, and fibrils (with turn-on ratios of 14 and 10 for Aβ42 and Aβ40, respectively). Mechanistic investigations were carried out by performing field-emission scanning electron microscopy, X-ray crystallography, UV-vis absorption spectroscopy, and steady-state and transient photoluminescence spectroscopy experiments. The studies revealed that the SN probes underwent preassembly prior to interacting with the Aβ species and that the preassembled structures depended profoundly on the subtle differences between the amino moieties of the different probes. Importantly, the studies demonstrated that the mode of fluorescence signaling (i.e., ratiometric response versus turn-on response) was primarily governed by stacking geometries within the probe preassemblies. Specifically, ratiometric fluorescence responses were observed for probes capable of forming J-assembly, whereas fluorescence turn-on responses were obtained for probes incapable of forming J-aggregates. This finding provides an important guideline to follow in future efforts at developing fluorescent probes for Aβ aggregation. We also conclude, on the basis of our study, that the rational design of such fluorescent probes should consider interactions between the probe molecules, as well as those between Aβ peptides and the probe molecule.

Original languageEnglish
Pages (from-to)5141-5154
Number of pages14
JournalACS Omega
Issue number5
StatePublished - 31 May 2018

Bibliographical note

Funding Information:
This work was supported by a grant from the Samsung Research Funding Center for Future Technology (SRFC-MA1301-01 to Y.Y.), the National Research Foundation of Korea (NRF-2017R1A2B3002585 and NRF-2016R1A5A1009405 to M.H.L. and NRF-2017R1A2B4005441 to J.C.), the Korea Advanced Institute of Science and Technology (to M.H.L.), and the Ministry of Science and ICT (DGIST R&D Program 18-BD-0403 to J.C.).

Publisher Copyright:
Copyright © 2018 American Chemical Society.


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