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Zinc oxide (ZnO) is a semiconductor metal oxide nanoparticle with inherent optical properties. Among the different zinc oxide nanostructures, nanoflowers have greater surface area. Utilizing this property a reagentless biosensor has been developed for the detection of beta amyloids, a hallmark of neurodegenerative diseases like Alzheimer's disease, Creutzfeldt-Jakob Syndrome, insulin dependent type II diabetes etc. The poor fluorescence quantum yield and photobleaching effect of Thioflavin T (ThT) upon binding to the model insulin amyloid beta sheets in solution can be overcome by the present engineered biosensor where ThT acts as a target as well as a reporter to detect amyloids adsorbed on a solid template based on ZnO nanoflower. ThT was adsorbed on ZnO NFs grown over nano-silver thin film coated glass slide. The in vivo imaging system was used to detect and quantify the fluorescence intensity generated from the substrates upon binding with insulin amyloid. ZnO NFs have the waveguiding property which increases the local field intensity caused by a resonance between the guided fundamental mode and evanescent field associated with high- order modes. This resonance phenomenon reinforces the excitation of the fluorophores in close proximity of the NFs thereby exhibiting enhanced fluorescence like Fabry Pero't Resonator (FPR). Considering the engineering and sensitivity, the reported nanobiosensor developed on ZnO nanoflower can be treated as faster and cost effective amyloid sensor. [ABSTRACT FROM AUTHOR]

For almost three decades, the application of Gd 3+ complexes as contrast-enhancing agents has largely contributed to the successful use of magnetic resonance imaging (MRI) both in the clinics and in biomedical research. More recently, the emergence of paramagnetic Chemical Exchange Saturation Transfer (ParaCEST) agents, most often based on lanthanide chelates, opened new possibilities to create MRI contrast. Via a judicious ligand design, the efficacy of Gd3+ complexes or the CEST effect of ParaCEST agents can be modulated by a variety of physical-chemical parameters (pH, temperature, ion concentration, etc.) or by interaction with biomarkers. This allows developing responsive probes, capable of reporting on different properties of the surrounding tissue. We survey recent contributions in the field of responsive probes for detection of enzymes, biologically important cations, or neurotransmitters. The specificity of a molecular probe can be improved by selectively delivering it to a specific target. Discrete MR probes can be adapted to visualize abundant targets. An important challenge is to retain the affinity of the vector for its target upon conjugation to paramagnetic chelates. These issues are discussed in the context of imaging of amyloid aggregates by Gd3+ complexes. To ascertain MRI findings, the possible detection of the probe in optical imaging is often explored. For this, imaging agents need to combine features required by MRI and optical imaging. We review approaches including both small molecular probes and nanoparticles. Finally, different nonconventional systems such as metal-organic frameworks, rotaxanes, or zeolites are discussed as potential MRI probes. [ABSTRACT FROM AUTHOR]

Cationic amyloid fibrils found in human semen enhance the transmission of the human immunodeficiency virus (HIV) and thus, are named semen-derived enhancer of virus infection (SEVI). The mechanism for the enhancement of transmission is not completely understood but it has been proposed that SEVI neutralizes the repulsion that exists between the negatively charged viral envelope and host cell membrane. Consistent with this view, here we show that the fluorescence of cationic thioflavin T (ThT) in the presence of SEVI is weak, and thus ThT is not an efficient detector of SEVI. On the other hand, K114 (( trans, trans)-bromo-2,5-bis(4-hydroxystyryl)benzene) forms a highly fluorescent, phenolate-like species on the cationic surface of SEVI. This species does not form in the presence of amyloid fibrils from insulin and amyloid-β protein, both of which are efficiently detected by ThT fluorescence. Together, our results show that K114 is an efficient detector of SEVI. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin, which can exist in an equilibrium between keto and enol tautomers, binds to β-amyloid (Aβ) fibrils/aggregates. The aim of this study was to assess the relationship between the tautomeric structures of curcumin derivatives and their Aβ-binding activities. Curcumin derivatives with keto-enol tautomerism showed high levels of binding to Aβ aggregates but not to Aβ monomers. The binding activity of the keto form analogue of curcumin to Aβ aggregates was found to be much weaker than that of curcumin derivatives with keto-enol tautomerism. The color of a curcumin derivative with keto-enol tautomerism, which was substituted at the C-4 position, changed from yellow to orange within 30 min of being combined with Aβ aggregates in physiological buffer. This resulted from a remarkable increase in the enol form with extended conjugation of double bonds upon binding. These findings suggest that curcumin derivatives exist predominantly in the enol form during binding to Aβ aggregates, and that the enolization of curcumin derivatives is crucial for binding to Aβ aggregates. The keto-enol tautomerism of curcumin derivatives may be a novel target for the design of amyloid-binding agents that can be used both for therapy and for amyloid detection in Alzheimer''s disease. [Copyright &y& Elsevier]

Here we present the TPA cross section and quantum efficiencies of a series of novel oligomeric luminescent conjugated polythiophenes used for detection and spectral diagnostics of amyloid protein aggregates of the amyloid-beta peptide associated with Alzheimer's disease. Specifically, these probes consist of pentameric or heptameric thiophenes derivatives with carboxylic substituents attached onto various thiophene rings. The probes absorbs over a broad range approx. 400-500 nm with quantum efficiency of approx. 20% in at neutral pH conditions, and also showed TPA cross sections of 5-50 GM in the range 700-840 nm, in the same order of magnitude as commonly used fluorescein derivatives, importantly, the multiphoton excitation capabilities of LCPs provided excellent performance when compared to imaging using conventional "single photon" excitation. It is also demonstrated their utilization in both one- and two-photon excitation laser scanning microscope spectral imaging for diagnostics of Alzheimer disease pathology in ex vivo histological sections. [ABSTRACT FROM AUTHOR]

Abstract: Amyloidosis producing insoluble fibrillar protein aggregates is the common pathological feature of various neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases in which α-synuclein and amyloid β/A4 protein (Aβ) participate to form Lewy bodies and senile plaques, respectively. To develop a novel analytical tool for amyloidosis, resveratrol, the major phenolic constituent of red wine and isolatable from grapevines, was employed to monitor the amyloids of α-synuclein and Aβ. Specific interaction to the amyloids enhanced the intrinsic fluorescence of resveratrol at 395 nm with an advent of new shoulder peak at 440 nm following an excitation at 320 nm. An increase in the resveratrol binding fluorescence was proportional to the quantity of amyloids. Typical sigmoidal kinetics of the amyloidosis of α-synuclein assessed with the thioflavin-T binding fluorescence or the β-sheet content was fully reproduced by the resveratrol binding fluorescence. The resveratrol binding to the amyloids became saturated as the dye concentration increased, whereas the enhanced thioflavin-T binding fluorescence was quenched by the unbound thioflavin-T at the high dye concentration. Because resveratrol does not require any adjustment of the amyloid/dye ratio to obtain optimal amyloid binding fluorescence, and it exerts a higher quantum yield than does thioflavin-T, resveratrol is suggested to be a specific and more reliable fluorescent probe to determine the amyloids quantitatively. [Copyright &y& Elsevier]

Anionic pentameric thiophene acetates can be used for fluorescence detection and diagnosis of protein amyloid aggregates. Replacing the central thiophene unit by benzothiadiazole (BTD) or quinoxaline (QX) leads to large emission shifts and basic spectral features have been reported [Chem. Eur. J. 2015, 21, 15133-13137]. Here we present new detailed experimental results of solvent effects, time-resolved fluorescence and examples employing multi-photon microscopy and lifetime imaging. Quantum chemical response calculations elucidate how the introduction of the BTD/QX groups changes the electronic states and emissions. The dramatic red-shift follows an increased conjugation and quinoid character of the π-electrons of the thiophene backbone. An efficient charge transfer in the excited states S 1 and S 2 compared to the all-thiophene analogue makes these more sensitive to the polarity and quenching by the solvent. Taken together, the results guide in the interpretation of images of stained Alzheimer disease brain sections employing advanced fluorescence microscopy and lifetime imaging, and can aid in optimizing future fluorescent ligand development., (© 2020 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Protein aggregation has been widely implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and Huntington disease, as well as in systemic amyloidoses and conditions associated with localized amyloid deposits, such as type-II diabetes. The pressing need for a better understanding of the factors governing protein assembly has driven research for the development of molecular sensors for amyloidogenic proteins. To date, a number of sensors have been developed that report on the presence of protein aggregates utilizing various modalities, and their utility demonstrated for imaging protein aggregation in vitro and in vivo . Analysis of these sensors highlights the various advantages and disadvantages of the different imaging modalities and makes clear that multimodal sensors with properties amenable to more than one imaging technique need to be developed. This critical review highlights the key molecular scaffolds reported for molecular imaging modalities such as fluorescence, positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging and includes discussion of the advantages and disadvantages of each modality, and future directions for the design of amyloid sensors. We also discuss the recent efforts focused on the design and development of multimodal sensors and the value of cross-validation across multiple modalities.

Staining with Congo Red (CR) is a qualitative method used for the identification of amyloids in vitro and in tissue sections. However, the drawbacks and artefacts obtained when using this dye can be found both in vitro and in vivo Analysis of scientific data from previous studies shows that CR staining alone is not sufficient for confirmation of the amyloid nature of protein aggregates in vitro or for diagnosis of amyloidosis in tissue sections. In the present paper, we describe the characteristics and limitations of other methods used for amyloid studies. Our historical review on the use of CR staining for amyloid studies may provide insight into the pitfalls and caveats related to this technique for researchers considering using this dye., (© 2019 The Author(s).)

Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Amyloid protein fibrillation is associated with a variety of neurodegenerative and other diseases, and their efficient detection and monitoring can greatly advance early diagnosis and therapy. Herein, we report a fluorescent "switch-on" probe for the reliable detection and monitoring of amyloid fibrils. The probe consists of a peptide component for binding with amyloid structure and a color component with an aggregation-induced green emission property. This probe is nonfluorescent in the presence of amyloid forming monomer protein/peptide, but fluorescence "switch-on" occurs after binding with amyloid fibrils. Compared to conventionally used thioflavin T, this probe offers a high signal-to-noise ratio, which is unaffected by the quencher ion/nanoparticle. The proposed new probe has been used for the detection and monitoring of amyloid fibrils produced by a wide variety of amyloid protein/peptides and can be extended for in vitro diagnostic applications.

Cationic amyloid fibrils found in human semen enhance the transmission of the human immunodeficiency virus (HIV) and thus, are named semen-derived enhancer of virus infection (SEVI). The mechanism for the enhancement of transmission is not completely understood but it has been proposed that SEVI neutralizes the repulsion that exists between the negatively charged viral envelope and host cell membrane. Consistent with this view, here we show that the fluorescence of cationic thioflavin T (ThT) in the presence of SEVI is weak, and thus ThT is not an efficient detector of SEVI. On the other hand, K114 ((trans, trans)-bromo-2,5-bis(4-hydroxystyryl)benzene) forms a highly fluorescent, phenolate-like species on the cationic surface of SEVI. This species does not form in the presence of amyloid fibrils from insulin and amyloid-β protein, both of which are efficiently detected by ThT fluorescence. Together, our results show that K114 is an efficient detector of SEVI., (© 2014 The Protein Society.)