Dataset Information

Development of amyloid beta gold nanorod aggregates as optoacoustic probes.

ABSTRACT: Propagation of small amyloid beta (Aβ) aggregates (or seeds) has been suggested as a potential mechanism of Alzheimer's disease progression. Monitoring the propagation of Aβ seeds in an organism would enable testing of this hypothesis and, if confirmed, provide mechanistic insights. This requires a contrast agent for long-term tracking of the seeds. Gold nanorods combine several attractive features for this challenging task, in particular, their strong absorbance in the infrared (enabling optoacoustic imaging) and the availability of several established protocols for surface functionalisation. In this work, polymer-coated gold nanorods were conjugated with anti-Aβ antibodies and attached to pre-formed Aβ seeds. The resulting complexes were characterised for their optical properties by UV/Vis spectroscopy and multispectral optoacoustic tomography. The complexes retained their biophysical properties, i.e. their ability to seed Aβ fibril formation. They remained stable in biological media for at least 2 days and showed no toxicity to SH-SY5Y neuroblastoma cells up to 1.5 nM and 6 μM of gold nanorods and Aβ seeds, respectively. Taken together, this study describes the first steps in the development of probes for monitoring the spread of Aβ seeds in animal models.

SUBMITTER: Soliman MG

PROVIDER: S-EPMC8956182 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Development of amyloid beta gold nanorod aggregates as optoacoustic probes.

Soliman Mahmoud G MG Davies Hannah A HA Sharkey Jack J Lévy Raphaël R Madine Jillian J

PloS one 20220325 3

Propagation of small amyloid beta (Aβ) aggregates (or seeds) has been suggested as a potential mechanism of Alzheimer's disease progression. Monitoring the propagation of Aβ seeds in an organism would enable testing of this hypothesis and, if confirmed, provide mechanistic insights. This requires a contrast agent for long-term tracking of the seeds. Gold nanorods combine several attractive features for this challenging task, in particular, their strong absorbance in the infrared (enabling optoac ...[more]

PMID: 35333865

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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

Development of amyloid beta gold nanorod aggregates as optoacoustic probes.

Publications

Development of amyloid beta gold nanorod aggregates as optoacoustic probes.

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