Oligo(ethylene glycol) Derivatives of Thioflavin T as Inhibitors of Protein–Amyloid Interactions

Inbar, Petra; Li, Cui Q.; Takayama, Stacy A; Bautista, Matthew; Yang, Jerry

doi:10.1002/cbic.200600119

Cited by 40 publications

(67 citation statements)

References 36 publications

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“…These observations are consistent with the hypothesis that H 2 O 2 , or its metabolites, but not superoxide, play a dominant role in 〈␤-induced oxidative stress. Moreover, Milton et al (21) and our previous work (55) revealed that 〈␤ binds directly to catalase in cell free assays, whereas 〈␤ does not bind to GPx (supplemental Fig. S12).…”

mentioning

confidence: 76%

“…These results are consistent with the possibility that the BTA-EG x molecules were capable of entering cells and could, hence, interact with intracellular pools of A␤ peptides. We hypothesize that this interaction between the BTA-EG x molecules and A␤ protected cells from harmful protein-amyloid interactions by forming protein-resistant molecular surface coatings on A␤ (55). Such a mechanism would explain the observed reduction in intracellular co-localization of catalase and A␤ in the presence of the BTA-EG x molecules.…”

Section: Bta-eg X Molecules Readily Internalize In Cells and Reduce Tmentioning

confidence: 90%

“…The results, however, do not rule out the possibility that amyloid interactions with proteins other than catalase could also contribute to cellular injury. We previously reported that BTA-EG 4 and BTA-EG 6 are capable of inhibiting several different A␤-binding proteins from associating with aggregated A␤ peptides (55). It is, therefore, likely that the BTA-EG x molecules in cells also attenuate harmful effects of A␤ on proteins other than catalase.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the fluorescence microscopy experiments and the co-immunoprecipitation experiments revealed a consistent trend for the slightly better performance of BTA-EG 4 for reducing the interaction of A␤ with catalase in cells compared with the BTA-EG 6 . We attribute this apparent enhanced performance of BTA-EG 4 to its increased lipophilicity compared with BTA-EG 6 (55), which may facilitate internalization in cells.…”

Section: Bta-eg X Molecules Readily Internalize In Cells and Reduce Tmentioning

confidence: 98%

“…We reported previously that BTA-EG 4 and BTA-EG 6 could inhibit catalase-A␤ binding interactions in solution by forming protein-resistant surface coatings on aggregated A␤(1-42) peptides (55). In order to determine whether these molecules could also protect the enzymatic activity of catalase in an A␤-rich environment, we developed an assay for quantifying catalase activity (see supplemental Fig.…”

Section: Bta-eg X Molecules Protect the H 2 O 2 -Degrading Activity Omentioning

confidence: 99%

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Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Habib

Lee

Yang

2010

Journal of Biological Chemistry

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102

120

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Although oxidative stress is commonly associated with aging (1, 2), patients with Alzheimer disease (AD) 3 often exhibit increased oxidative damage (3-10) and subsequent neuronal loss in ␤-amyloid (A␤)-rich regions of the brain. The molecular mechanisms by which A␤ contributes to oxidative damage remain unclear (11)(12)(13)(14)(15)(16)(17)(18)(19). Understanding these mechanisms, however, is critical for developing effective methods to manage the disease. One mechanism for A␤-induced cellular oxidative stress proposes that A␤ peptides interact directly with cellular enzymes responsible for maintaining low physiological levels of reactive oxygen species (ROS) (20 -23). Two potential outcomes from such pathological protein-amyloid interactions are: 1) increased production of ROS, or 2) reduced degradation of ROS.The major ROS in cells are superoxide and the more reactive hydrogen peroxide (H 2 O 2 )-derived hydroxyl radical (24, 25). Both superoxide and H 2 O 2 are primarily produced in the mitochondria (26 -28). A␤ peptides have been shown to accumulate in the mitochondria (29, 30), and, therefore, could exert their detrimental effects through interaction with mitochondrial proteins (23, 31-34). Superoxide is produced by several enzymecatalyzed reactions in the mitochondria (25). Behl et al. (11) however, showed that a broad range of inhibitors of several of these enzymes had no effect on 〈␤ toxicity in clonal and primary neuronal cell cultures. Furthermore, Zhang et al. (35) reported that superoxide levels in cells were not substantially elevated upon exposure to 〈␤. These findings suggest that superoxide is not a dominant contributor to 〈␤ toxicity.On the other hand, 〈␤-induced cellular increase in H 2 O 2 or its metabolites is strongly correlated with 〈␤ toxicity (11, 13, 36). H 2 O 2 can be generated by several mitochondrial enzymes including monoamine oxidases, superoxide dismutase, and xanthine oxidase (25). Behl et al. (11) showed that inhibitors of monoamine oxidases and xanthine oxidase had no effect on 〈␤-induced H 2 O 2 accumulation or 〈␤ toxicity. Gsell et al. (37) also found that the activity of superoxide dismutase was unaltered in the brains of AD patients. Additionally, Rensink et al. (38) reported that the Dutch mutation of 〈␤ peptides (HCHWA-D 〈␤) did not bind directly to superoxide dismutase and Kaminsky et al. (39) reported only a relatively small effect of 〈␤ on superoxide dismutase activity and H 2 O 2 production upon chronic exposure of rat brains to 〈␤. These results suggest that 〈␤ peptides do not significantly affect production of H 2 O 2 in cells. Consequently, these findings imply that 〈␤-induced oxidative stress may arise from reduced degradation of H 2 O 2 in 〈␤-challenged cells.Degradation of H 2 O 2 in cells is primarily achieved by the enzymes catalase and glutathione peroxidase (GPx), both inside and outside of the mitochondria (25). Sagara et al. (40) found that cells resistant to 〈␤ toxicity had elevated levels of catalase and GPx. The activity of both enzymes was redu...

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mentioning

confidence: 76%

Section: Bta-eg X Molecules Readily Internalize In Cells and Reduce Tmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Bta-eg X Molecules Readily Internalize In Cells and Reduce Tmentioning

confidence: 98%

Section: Bta-eg X Molecules Protect the H 2 O 2 -Degrading Activity Omentioning

confidence: 99%

See 3 more Smart Citations

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Habib

Lee

Yang

2010

Journal of Biological Chemistry

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102

120

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Rational Design of Amyloid Binding Agents Based on the Molecular Rotor Motif

et al. 2009

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Alzheimer's disease (AD) is characterized by a progressive loss of cognitive function and constitutes the most common and fatal neurodegenerative disorder.[1] Genetic and clinical evidence supports the hypothesis that accumulation of amyloid deposits in the brain plays an important role in the pathology of the disease. This event is associated with perturbations of biological functions in the surrounding tissue leading to neuronal cell death, thus contributing to the disease process. The deposits are comprised primarily of amyloid (Aβ) peptides, a 39-43 amino acid sequence that self aggregates into a fibrillar β-pleated sheet motif. While the exact three-dimensional structure of the aggregated Aβ peptides is not known, a model structure that sustains the property of aggregation has been proposed. [2] This creates opportunities for in vivo imaging of amyloid deposits that can not only help evaluate the time course and evolution of the disease, but can also allow the timely monitoring of therapeutic treatments. [3] Keywords amyloid peptides; fluorescent probes; imaging agents; molecular rotors Historically, Congo Red (CR) and Thioflavin T (ThT) have provided the starting point for the visualization of amyloid plaques and are still commonly employed in post mortem histological analyses (Figure 1).[4] However, due to their charge these probes are unsuitable for in vivo applications. [5] To address this issue, several laboratories developed probes with noncharged, lipophilic (log P = 0.1-3.5) and low-molecular weight chemical structures (MW <650) that facilitate crossing of the blood-brain barrier.[6] Further functionalization of these compounds with radionuclides led to a new generation of in vivo diagnostic reagents (Figure 1) that target plaques and related structures for imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT Figure 1 reveals that the majority of these probes contain an electrondonor unit in conjugation with an electron acceptor (D-π-A motif). This motif is a typical feature in molecular rotors, a family of fluorescent probes known to form twisted intramolecular charge-transfer (TICT) complexes in the excited state producing a fluorescence quantum yield that is dependent on the surrounding environment.[11] Following photoexcitation, this motif has the unique ability to relax either via fluorescence emission or via an internal nonradiative molecular rotation. This internal rotation occurs around the σ-bonds that connect the electron-rich π-system with the donor and acceptor groups, and can be modified by altering the chemical structure and microenvironment of the probe.[12] Hindrance of the internal molecular rotation of the probe by increasing the surrounding media rigidity, or by reducing the available free volume needed for relaxation, leads to a decrease in the nonradiative decay rate and consequently an increase in fluorescence. In contrast, relaxation proceeds mainly via nonradiative pathways in environments of low viscosity or of hi...

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Small-Molecule Mediated Neuroprotection in an In Situ Model of Tauopathy

et al. 2009

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Small-molecule inhibitors of neurofibrillary lesion formation may have utility for treatment of Alzheimer’s disease and certain forms of frontotemporal lobar degeneration. These lesions are composed largely of tau protein, which aggregates to form intracellular fibrils in affected neurons. Previously it was shown that chronic overexpression of human tau protein within identified neurons (anterior bulbar cells) of the sea lamprey induced a phenotype resembling tauopathic neurodegeneration, including the formation of tau filaments, fragmentation of dendritic arbors, and eventual cell death. Development of this neurodegenerative phenotype was blocked by chronic administration of a benzothiazole derivative termed N3 ((E)-2-[[4-(dimethylamino)phenyl]azo]-6-methoxybenzothiazole) to lamprey aquaria. Here we examined the mechanism of action of N3 and an alkene analog termed N4 ((E)-2-[2-[4-(dimethylamino)phenyl]ethenyl]-6-methoxybenzothiazole) in vitro and in the lamprey model. Results showed that although both compounds entered the lamprey central nervous system, only N3 arrested tauopathy. On the basis of in vitro aggregation assays, neither compound was capable of directly inhibiting tau filament formation. However N3, but not N4, was capable of partially antagonizing the binding of Thioflavin S to synthetic tau filaments. The results suggest that occupancy of N3 binding sites on nascent tau filaments may significantly retard the progressive degeneration accompanying tau overexpression in lamprey.

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Oligo(ethylene glycol) Derivatives of Thioflavin T as Inhibitors of Protein–Amyloid Interactions

Cited by 40 publications

References 36 publications

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Rational Design of Amyloid Binding Agents Based on the Molecular Rotor Motif

Small-Molecule Mediated Neuroprotection in an In Situ Model of Tauopathy

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