Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status

Groenning, Minna

doi:10.1007/s12154-009-0027-5

Cited by 564 publications

(601 citation statements)

References 164 publications

(393 reference statements)

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“…It is known that DAPI binds to some kind of protein (13 -15). Recently, many molecular probes for amyloid fibrils have been reported (16,17). Some 2 -phenylindole derivatives are known as such probes (18), but as far as we know, there are no reports that DAPI can be used as a diagnostic dye for renal amyloidosis.…”

Section: Discussionmentioning

confidence: 99%

A Novel Method of DAPI Staining for Differential Diagnosis of Renal Amyloidosis

et al. 2017

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Section: Discussionmentioning

confidence: 99%

A Novel Method of DAPI Staining for Differential Diagnosis of Renal Amyloidosis

et al. 2017

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“…Dyes such as thioflavin Tand Congo red tend to bind to amyloid structures, causing changes in their spectrophotometric properties. Although these dyes are generally specific enough to be used as diagnostic tools, varying binding modes are possible depending on the fibril type, which may cause false positive or negative results (Groenning 2010). Evidence suggests that, although large amyloid fibrils physically disrupt organelles and tissues, smaller aggregates are more toxic (Buxbaum 2004;Bitan et al 2005).…”

Section: How Would the Amyloid Aggregation Of P53 Contribute To Oncogmentioning

confidence: 99%

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Costa

Oliveira

Cino

et al. 2016

Cold Spring Harb Perspect Biol

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Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

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“…At a low concentration (25 nM) and in the presence of Aβ 42 , 3 shows a significant emission signal ( Figure 2B) without affecting the ThT excitation and emission profile ( Figure 2C). Conversely, at higher concentrations, 3 progressively displaces ThT from its binding site(s) 24 ( Figure S2 in the Supporting Information). This led us to hypothesize that 3 may have a primary high affinity binding site distinct from ThT and a secondary low-affinity binding site in common with ThT.…”

Section: * S Supporting Informationmentioning

confidence: 99%

A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer’s and Prion Diseases

Staderini

Aulić

Bartolini

et al. 2013

ACS Med. Chem. Lett.

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(E)-6-Methyl-4′-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aβ and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aβ self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).KEYWORDS: Aggregation, protein misfolding diseases, amyloid, fibrillation inhibitors P rotein misfolding diseases (PMD) include a broad range of human disorders characterized by a conformational change of normally expressed proteins, that convert from a physiological soluble monomeric form into oligomeric and fibrillar forms, rich in stable β-sheet regions. 1 These fibrillar aggregates play a pivotal role in neuronal dysfunction and survival, eventually leading to fatal disease. Alzheimer's (AD) and prion diseases (PrD) are prototypical examples of PMD. In these maladies, amyloid-β protein (Aβ) and cellular prion protein (PrP C ), respectively, change their conformations into β-sheet toxic isoforms. In the case of PrD, the toxic isoform known as scrapie prion protein (PrP Sc ) is also infectious. 2 In AD and PrD, the misfolded proteins have been regarded both as neuropathological hallmarks for diagnosis and as therapeutic targets. 2 While the so-called "amyloid hypothesis" in AD has been questioned, a recent interest has arisen in the possibility that all proteins causing neurodegeneration are prions. 2 If confirmed, this hypothesis would profoundly influence the development of diagnostic and therapeutic tools. 2 Many techniques have been employed to detect fibrillar aggregates, including positron emission tomography (PET) 3 and fluorescence spectroscopy. 4 PET is expensive and limited by the narrow isotope availability of the required probes. On the other hand, many fluorescent in vitro staining agents are available such as Congo Red (CR) and Thioflavin T (ThT) but they cannot translate into clinical diagnostic and therapeutic tools 4 because of their low specificity, poor sensitivity, inability to cross the blood brain barrier (BBB) and marked toxicity. 5 Because fluorescence spectroscopy has proven suitable for studying fibrillar aggregates also in vivo, 6−9 there is an urgent need for fluorescent sensors with improved properties.With these concepts in mind, we focused our attention on fluorescent compounds capable of staining Aβ and PrP Sc fibrils and, ideally, of simultaneously blocking their aggregation. To this aim, ideal properties for a therapeutic and diagnostic small molecule should include (1) ability to change fluorescence properties upon binding to fibrils, (2) ability to absorb and emit light in the far red/near-infrared (NIR) region (ca. 600−800 nm), 7 where tissue scattering and absorption is lowest...

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Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status

Cited by 564 publications

References 164 publications

A Novel Method of DAPI Staining for Differential Diagnosis of Renal Amyloidosis

A Novel Method of DAPI Staining for Differential Diagnosis of Renal Amyloidosis

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer’s and Prion Diseases

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