Differentiating Aβ40 and Aβ42 in amyloid plaques with a small molecule fluorescence probe

Yang, Jing; Zhu, Biyue; Yin, Wei; Han, Zhihao; Zheng, Chao; Wang, Peng; Ran, Chongzhao

doi:10.1039/d0sc02060e

Cited by 33 publications

(26 citation statements)

References 51 publications

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“…As shown in Figure 3 B, the fluorescence intensity of probe 2 could linearly correlate with Aβ monomers, oligomers and aggregates at a concentration range of 100 nM-6.4 μM, 50 nM-3.2 μM and 100 nM-10 μM, respectively. The LOD (3σ/k) was then calculated to be ~14.1, ~12.8 and ~12.9 nM for the monomers, oligomers and aggregates, respectively, which were comparable to that of other previously reported fluorescent probes for Aβ aggregates 28 , 49 - 53 . Third, the examination of the selectivity toward the Aβ proteins over other representative endogenous species, including L -Cysteine, glutathione, vitamin C, Cytochrome C, BSA, AChE, BuChE, Amylin, hMAO-A, β-Galactosidase, and reactive oxygen species (hydroxyl radical, singlet oxygen, superoxide radical, and H 2 O 2 ) showed that strong fluorescence could be observed only in the presence of Aβ monomers, oligomers or aggregates; negligible fluorescence appeared toward other examined species, especially Amylin or BSA, which were found to be notorious species potentially competing with the Aβ species in the brain (Figure 3 C).…”

Section: Resultssupporting

confidence: 80%

Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-β species

Fang¹,

Wen²,

Wang³

et al. 2022

Theranostics

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Near-infrared (NIR) fluorescent imaging of both soluble and insoluble Aβ species in the brain of Alzheimer's disease (AD) is crucial for the early diagnosis and intervention of AD. To date, a variety of NIR fluorescent probes have been reported for the detection of Aβ species. Among these probes, CRANAD-58 was reported to have the capability to detect both soluble and insoluble Aβ species, which is vital to monitor the changes of Aβ species during the pathological course of the disease. Though CRANAD-58 has shown promise to noninvasively detect Aβ species in transgenic AD mice, the emission wavelength (~670 nm) is still too short for further applications. Therefore, new probes with longer emission wavelength and improved physiological properties are in highly demand. Herein, we report the design and engineering of nine donor-acceptor-donor molecules as “off-on” near-infrared fluorescent probes for in vivo imaging of both soluble and insoluble Aβ species in living AD mice owing to its improved in vitro properties and in vivo performance. Methods: We report a two-round strategy to develop nine “off-on” NIR fluorescence probes via structural modification of a curcumin analogue-based donor-acceptor-donor architecture. In round one, probes 1 and 2 were synthesized, and probe 2 was identified to be an optimum probe as it showed distinct “off-on” NIR fluorescence at > 690 nm upon binding to Aβ monomers, oligomers and aggregates. To further improve the in vivo performance, further structural modification of probe 2 into probes 3 - 9 was then conducted. The fluorescence response with Aβ species and histological staining in vitro and in vivo imaging of Aβ species in APP/PS1 transgenic AD mice and age-matched wild-type mice were performed. Results: We demonstrate that, compared to probe 2 , probe 9 with improved physiological properties hold the fastest kinetics (~10 min) to produce not only higher brain fluorescence intensity in 10-month-old APP/PS1 transgenic AD mice, but also afford a higher discrepancy in brain fluorescence to discriminate AD mice from wild-type (WT) mice. Probe 9 also hold the ability to detect soluble Aβ species in 6-month-old APP/PS1 transgenic mice. Probe 9 was further applied for dynamic visualization of Aβ plaques in a skull-thinning 14-month-old APP/PS1 mouse, which revealed its immediate penetration into brain parenchyma and selective labeling of both parenchymal and angiopathic Aβ plaques. In addition, probe 9 possessed significantly high attenuation effect on the aggregation of Aβ monomers. Conclusion: Our results demonstrate the goo...

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Section: Resultssupporting

confidence: 80%

Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-β species

Fang¹,

Wen²,

Wang³

et al. 2022

Theranostics

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“…More specifically, they can form hydrogen bonds and salt bridges with the amino acids Asp1 and Ala42. Their binding motif is similar to that of the fluorescent probe reported by the Ran group, which can differentiate Aβ42 fibrils and Aβ40 fibrils by targeting the extra two amino acids at the C terminal of the Aβ42 fibrils, suggesting that ZY-17-DT and ZY-17-OMe might also have a different binding affinity towards Aβ42 vs. Aβ40 fibrils 42.…”

supporting

confidence: 71%

Amphiphilic Stilbene Derivatives Attenuate the Neurotoxicity of Soluble Aβ42 Oligomers by Controlling Their Interactions with Cell Membranes

Yu¹,

Guo²,

Cho³

et al. 2021

Preprint

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Misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer’s disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-β (Aβ) plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro binding experiments (i.e., fluorescence saturation assays) demonstrated that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit even higher binding affinity toward Aβ oligomers. These amphiphilic compounds can also <a>label ex vivo Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. </a>Molecular docking studies were performed to help understand the structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate Cu2+-Aβ induced toxicity in mouse neuroblastoma N2a via cell toxicity assays. In addition, <a>confocal</a> fluorescence imaging studies provided evidence that compounds ZY-15-MT and ZY-15-OMe can disrupt <a>the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell</a> membranes. Overall, these studies suggest that developing compounds with amphiphilic properties that target Aβ oligomers can be an effective strategy for small molecule AD therapeutics.

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“…[ 175 ] Development of novel A β plaque‐targeting fluorescent imaging agents has become a hot topic. [ 176,177 ] Marzano et al investigated an acrylonitrile derivative 118 (Figure 20) for aggregation‐induced emission properties as a fluorescent imaging agent to detect amyloid fibrils. It was reported that this compound stained oligomeric and pre‐fibrillar species of amyloidogenic α ‐synuclein with higher affinity compared to thioflavin‐T.…”

Section: Biological Activities Of Acrylonitrilesmentioning

confidence: 99%

Insights into the chemistry and therapeutic potential of acrylonitrile derivatives

Tan

Zengin

2021

Archiv der Pharmazie

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Acrylonitrile is a fascinating scaffold widely found in many natural products, drugs, and drug candidates with various biological activities. Several drug molecules such as entacapone, rilpivirine, teriflunomide, and so forth, bearing an acrylonitrile moiety have been marketed. In this review, diverse synthetic strategies for constructing desired acrylonitriles are discussed, and the different biological activities and medicinal significance of various acrylonitrile derivatives are critically evaluated. The information gathered is expected to provide rational guidance for the development of clinically useful agents from acrylonitriles.

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Differentiating Aβ40 and Aβ42 in amyloid plaques with a small molecule fluorescence probe

Abstract: A small molecule fluorescence probe ICTAD-1 was rationally designed for differentiating Aβ40 and Aβ42 in solutions and in Aβ plaques.

Cited by 33 publications

References 51 publications

Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-β species

Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-β species

Amphiphilic Stilbene Derivatives Attenuate the Neurotoxicity of Soluble Aβ42 Oligomers by Controlling Their Interactions with Cell Membranes

Insights into the chemistry and therapeutic potential of acrylonitrile derivatives

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