Dataset Information

Monitoring amyloid aggregation via a twisted intramolecular charge transfer (TICT)-based fluorescent sensor array.

ABSTRACT: Imaging amyloid-beta (Aβ) aggregation is critical for understanding the pathology and aiding the pre-symptomatic intervention of Alzheimer's disease (AD). Amyloid aggregation consists of multiple phases with increasing viscosities and demands probes with broad dynamic ranges and gradient sensitivities for continuous monitoring. Yet, existing probes designed based on the twisted intramolecular charge transfer (TICT) mechanism mainly focused on donor engineering, limiting the sensitivities and/or dynamic ranges of these fluorophores to a narrow window. Herein, using quantum chemical calculations, we investigated multiple factors affecting the TICT process of fluorophores. It includes the conjugation length, the net charge of the fluorophore scaffold, the donor strength, and the geometric pre-twisting. We have established an integrative framework for tuning TICT tendencies. Based on this framework, a platter of hemicyanines with varied sensitivities and dynamic ranges is synthesized, forming a sensor array and enabling the observation of various stages of Aβ aggregations. This approach will significantly facilitate the development of TICT-based fluorescent probes with tailored environmental sensitivities for numerous applications.

SUBMITTER: Wang C

PROVIDER: S-EPMC10171079 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Monitoring amyloid aggregation <i>via</i> a twisted intramolecular charge transfer (TICT)-based fluorescent sensor array.

Wang Chao C Jiang Wenchao W Tan Davin D Huang Lu L Li Jin J Qiao Qinglong Q Yadav Priya P Liu Xiaogang X Xu Zhaochao Z

Chemical science 20230405 18

Imaging amyloid-beta (Aβ) aggregation is critical for understanding the pathology and aiding the pre-symptomatic intervention of Alzheimer's disease (AD). Amyloid aggregation consists of multiple phases with increasing viscosities and demands probes with broad dynamic ranges and gradient sensitivities for continuous monitoring. Yet, existing probes designed based on the twisted intramolecular charge transfer (TICT) mechanism mainly focused on donor engineering, limiting the sensitivities and/or ...[more]

PMID: 37181777

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Project description: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 (Δν = 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.

Dataset Information

Monitoring amyloid aggregation via a twisted intramolecular charge transfer (TICT)-based fluorescent sensor array.

Publications

Monitoring amyloid aggregation <i>via</i> a twisted intramolecular charge transfer (TICT)-based fluorescent sensor array.

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