A Strategy for Designing a Peptide Probe for Detection of β‐Amyloid Oligomers

Hu, Yang; Su, Baihao; Kim, Chung Sei; Hernandez, Michael; Rostagno, Agueda; Ghiso, Jorge; Kim, Jin Ryoun

doi:10.1002/cbic.201000435

Cited by 43 publications

(57 citation statements)

References 70 publications

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“…The TEM image of Aβ monomers incubated for 5 days also clearly show the existence of the Aβ aggregates consisting of protofibrils and short fibrils (Figure 4; Panel Aβ only). Recently, dot-blotting with Aβ-specific antibodies was widely used to detect the spectrum of Aβ aggregates with different conformations [16], [27], [37], [57], [58], [59], [60]. OC is a polyclonal antibody that reacts with neurotoxic fibrillar oligomers, protofibrils and fibrils [16], [58].…”

Section: Resultsmentioning

confidence: 99%

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

2013

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Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates. Moreover, halogenation of aromatic molecules greatly affects aromatic interaction-mediated self-assembly processes, including amyloid fibril formation. Perturbation of the aromatic interaction caused by halogenation of peptide building blocks is known to affect the morphology and other physical properties of the fibrillar structure. Consequently, in this article, we investigated the ability of halogenated ligands to modulate the self-assembly of amyloidogenic peptide/protein. As a model system, we chose amyloid-beta peptide (Aβ), which is implicated in Alzheimer’s disease, and a novel modulator of Aβ aggregation, erythrosine B (ERB). Considering that four halogen atoms are attached to the xanthene benzoate group in ERB, we hypothesized that halogenation of the xanthene benzoate plays a critical role in modulating Aβ aggregation and cytotoxicity. Therefore, we evaluated the modulating capacities of four ERB analogs containing different types and numbers of halogen atoms as well as fluorescein as a negative control. We found that fluorescein is not an effective modulator of Aβ aggregation and cytotoxicity. However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation. Such Aβ aggregation inhibition by ERB analogs except rose bengal correlated well to the inhibition of Aβ cytotoxicity. To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.

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Section: Resultsmentioning

confidence: 99%

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

2013

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“…These assays were performed to obtain an integrated picture of Aβ aggregation modulation by ER. With Aβ-specific antibodies, dot blotting has become an effective method for monitoring Aβ aggregate formation [1], [26], [27], [28], [29], [30]. Four Aβ-specific antibodies were utilized for this purpose.…”

Section: Resultsmentioning

confidence: 99%

“…6E10 is a monoclonal antibody that recognizes Aβ residues 1-16 [28], [35]. A11 is a polyclonal antibody that reacts with soluble toxic oligomers and protofibrils [7], [28], [30]. OC is a polyclonal antibody that reacts with aggregates with fibrillar structure, including fibrillar oligomers, protofibrils and fibrils [28], [29].…”

Section: Resultsmentioning

confidence: 99%

Xanthene Food Dye, as a Modulator of Alzheimer's Disease Amyloid-beta Peptide Aggregation and the Associated Impaired Neuronal Cell Function

Wong

Kwon

2011

PLoS ONE

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BackgroundAlzheimer's disease (AD) is the most common form of dementia. AD is a degenerative brain disorder that causes problems with memory, thinking and behavior. It has been suggested that aggregation of amyloid-beta peptide (Aβ) is closely linked to the development of AD pathology. In the search for safe, effective modulators, we evaluated the modulating capabilities of erythrosine B (ER), a Food and Drug Administration (FDA)-approved red food dye, on Aβ aggregation and Aβ-associated impaired neuronal cell function.Methodology/Principal FindingsIn order to evaluate the modulating ability of ER on Aβ aggregation, we employed transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assay, and immunoassays using Aβ-specific antibodies. TEM images and ThT fluorescence of Aβ samples indicate that protofibrils are predominantly generated and persist for at least 3 days. The average length of the ER-induced protofibrils is inversely proportional to the concentration of ER above the stoichiometric concentration of Aβ monomers. Immunoassay results using Aβ-specific antibodies suggest that ER binds to the N-terminus of Aβ and inhibits amyloid fibril formation. In order to evaluate Aβ-associated toxicity we determined the reducing activity of SH-SY5Y neuroblastoma cells treated with Aβ aggregates formed in the absence or in the presence of ER. As the concentration of ER increased above the stoichiometric concentration of Aβ, cellular reducing activity increased and Aβ-associated reducing activity loss was negligible at 500 µM ER.Conclusions/SignificanceOur findings show that ER is a novel modulator of Aβ aggregation and reduces Aβ-associated impaired cell function. Our findings also suggest that xanthene dye can be a new type of small molecule modulator of Aβ aggregation. With demonstrated safety profiles and blood-brain permeability, ER represents a particularly attractive aggregation modulator for amyloidogenic proteins associated with neurodegenerative diseases.

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“…8 Despite extensive research for many decades, it was only until recently that a brain imaging agent, Florbetapir, was approved by the Food and Drug Administration (FDA) to evaluate AD. 9 In recent years, however, there has been a paradigm shift with numerous reported efforts involved in the development of effective methods for Aβ oligomers detection, including oligomer-specific antibody, 10 oligomer-specific peptide-FlAsh system, 11,12 peptide-based fluorescent protein, 13 as well as the ELISA method. 14 Yet, these detection methods often involve laborious construction methods, complicated instrumentation, or a long testing time, which make them inconvenient to use.…”

Section: Introductionmentioning

confidence: 99%

Chemical Fluorescent Probe for Detection of Aβ Oligomers

et al. 2015

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Aggregation of amyloid β-peptide (Aβ) is implicated in the pathology of Alzheimer’s disease (AD), with the soluble, Aβ oligomeric species thought to be the critical pathological species. Identification and characterization of intermediate species formed during the aggregation process is crucial to the understanding of the mechanisms by which oligomeric species mediate neuronal toxicity and following disease progression. Probing these species proved to be extremely challenging, as evident by the lack of reliable sensors, due to their heterogeneous and transient nature. We describe here an oligomer-specific fluorescent chemical probe, BoDipy-Oligomer (BD-Oligo), developed through the use of the diversity-oriented fluorescent library approach (DOFLA) and high-content, imaging-based screening. This probe enables dynamic oligomer monitoring during fibrillogenesis in vitro and shows in vivo Aβ oligomers staining possibility in the AD mice model.

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A Strategy for Designing a Peptide Probe for Detection of β‐Amyloid Oligomers

Cited by 43 publications

References 70 publications

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

Xanthene Food Dye, as a Modulator of Alzheimer's Disease Amyloid-beta Peptide Aggregation and the Associated Impaired Neuronal Cell Function

Chemical Fluorescent Probe for Detection of Aβ Oligomers

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