Dataset Information

ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

ABSTRACT: A new family of fluorescent markers containing an Amino Naphthalenyl-2-Cyano-Acrylate (ANCA) motif has been synthesized and evaluated for its capability to associate with aggregated β-amyloid (Aβ) peptides. These fluorescent probes contain a nitrogen donor group that is connected via a naphthalene unit to an electron acceptor motif containing Water Solubilizing Groups (WSG). Chemical modifications were introduced to explore their effect on the capability of the ANCA-based probes to fluorescently label aggregated Aβ peptides. All synthesized probes bind to aggregated Aβ fibrils with low micromolar affinity and fluorescently stain amyloid deposits in human brain tissue from patients with Alzheimer's disease. We found that structural modifications of the WSG site do not affect considerably the binding affinity. However, changes of the nitrogen donor group alter significantly the binding affinity of these probes. Also, increasing the hydrophilicity of the donor group leads to improved contrast between the Aβ deposits and the surrounding tissue in histological staining experiments.

SUBMITTER: Chang WM

PROVIDER: S-EPMC3129977 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

Chang Willy M WM Dakanali Marianna M Capule Christina C CC Sigurdson Christina J CJ Yang Jerry J Theodorakis Emmanuel A EA

ACS chemical neuroscience 20110501 5

A new family of fluorescent markers containing an Amino Naphthalenyl-2-Cyano-Acrylate (ANCA) motif has been synthesized and evaluated for its capability to associate with aggregated β-amyloid (Aβ) peptides. These fluorescent probes contain a nitrogen donor group that is connected via a naphthalene unit to an electron acceptor motif containing Water Solubilizing Groups (WSG). Chemical modifications were introduced to explore their effect on the capability of the ANCA-based probes to fluorescently ...[more]

PMID: 21743829

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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

ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

Publications

ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

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