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Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-β aggregation and toxicity.

ABSTRACT: Cytochrome c (Cyt c), a multifunctional protein with a crucial role in controlling cell fate, has been implicated in the amyloid pathology associated with Alzheimer's disease (AD); however, the interaction between Cyt c and amyloid-β (Aβ) with the consequent impact on the aggregation and toxicity of Aβ is not known. Here we report that Cyt c can directly bind to Aβ and alter the aggregation and toxicity profiles of Aβ in a manner that is dependent on the presence of a peroxide. When combined with hydrogen peroxide (H₂O₂), Cyt c redirects Aβ peptides into less toxic, off-pathway amorphous aggregates, whereas without H₂O₂, it promotes Aβ fibrillization. The mechanisms behind these effects may involve a combination of the complexation between Cyt c and Aβ, the oxidation of Aβ by Cyt c and H₂O₂, and the modification of Cyt c by H₂O₂. Our findings demonstrate a new function of Cyt c as a modulator against Aβ amyloidogenesis.

SUBMITTER: Du Z

PROVIDER: S-EPMC10208028 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-β aggregation and toxicity.

Du Zhi Z Nam Eunju E Lin Yuxi Y Hong Mannkyu M Molnár Tamás T Kondo Ikufumi I Ishimori Koichiro K Baik Mu-Hyun MH Lee Young-Ho YH Lim Mi Hee MH

Chemical science 20230425 20

Cytochrome c (Cyt c), a multifunctional protein with a crucial role in controlling cell fate, has been implicated in the amyloid pathology associated with Alzheimer's disease (AD); however, the interaction between Cyt c and amyloid-β (Aβ) with the consequent impact on the aggregation and toxicity of Aβ is not known. Here we report that Cyt c can directly bind to Aβ and alter the aggregation and toxicity profiles of Aβ in a manner that is dependent on the presence of a ...[more]

PMID: 37234895

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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

Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-β aggregation and toxicity.

Publications

Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-β aggregation and toxicity.

Similar Datasets

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