Abstract
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.
Highlights
Growing evidence suggests that protein misfolding and aggregation closely correlate to the onset of numerous neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD)
amyloid-beta peptide (Ab) intermediates as well as fibrils can be directly visualized with negative-stain transmission electron microscopy (TEM)
thioflavin T (ThT) fluorescence is used to monitor the progression of amyloid fibril formation
Summary
Growing evidence suggests that protein misfolding and aggregation closely correlate to the onset of numerous neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Wanker et al reported that (-)epigallocatechin gallate preferentially binds to unfolded monomeric a-synuclein and Ab and induces formation of non-toxic oligomers, suggesting that small molecules modulate aggregation of amyloidogenic proteins through a common molecular mechanism [7]. We evaluate the modulating capacities of ER on Ab aggregation and Ab-induced impaired cellular reducing activity in neuronal cells, and investigate whether there are any common features in the interaction mode of erythrosine B with between a-synuclein and Ab. ER is a xanthene dye and is commonly used in coloring candies and cakes (Figure 1).
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