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A safe, blood-brain barrier permeable triphenylmethane dye inhibits amyloid-? neurotoxicity by generating nontoxic aggregates.

ABSTRACT: Growing evidence suggests that on-pathway amyloid-? (A?) oligomers are primary neurotoxic species and have a direct correlation with the onset of Alzheimer's disease (AD). One promising therapeutic strategy to block AD progression is to reduce the levels of these neurotoxic A? species using small molecules. While several compounds have been shown to modulate A? aggregation, compounds with such activity combined with safety and high blood-brain barrier (BBB) permeability have yet to be reported. Brilliant Blue G (BBG) is a close structural analogue of a U.S. Food and Drug Administration (FDA)-approved food dye and has recently garnered prominent attention as a potential drug to treat spinal cord injury due to its neuroprotective effects along with BBB permeability and high degree of safety. In this work, we demonstrate that BBG is an effective A? aggregation modulator, which reduces A?-associated cytotoxicity in a dose-dependent manner by promoting the formation of off-pathway, nontoxic aggregates. Comparative studies of BBG and three structural analogues, Brilliant Blue R (BBR), Brilliant Blue FCF (BBF), and Fast Green FCF (FGF), revealed that BBG is most effective, BBR is moderately effective, and BBF and FGF are least effective in modulating A? aggregation and cytotoxicity. Therefore, the two additional methyl groups of BBG and other structural differences between the congeners are important in the interaction of BBG with A? leading to formation of nontoxic A? aggregates. Our findings support the hypothesis that generating nontoxic aggregates using small molecule modulators is an effective strategy for reducing A? cytotoxicity. Furthermore, key structural features of BBG identified through structure-function studies can open new avenues into therapeutic design for combating AD.

SUBMITTER: Wong HE

PROVIDER: S-EPMC3369715 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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A safe, blood-brain barrier permeable triphenylmethane dye inhibits amyloid-β neurotoxicity by generating nontoxic aggregates.

Wong H Edward HE Qi Wei W Choi Hyung-Min HM Fernandez Erik J EJ Kwon Inchan I

ACS chemical neuroscience 20110906 11

Growing evidence suggests that on-pathway amyloid-β (Aβ) oligomers are primary neurotoxic species and have a direct correlation with the onset of Alzheimer's disease (AD). One promising therapeutic strategy to block AD progression is to reduce the levels of these neurotoxic Aβ species using small molecules. While several compounds have been shown to modulate Aβ aggregation, compounds with such activity combined with safety and high blood-brain barrier (BBB) permeability have yet to be reported. ...[more]

PMID: 22860159

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Project description:Proteins containing polyglutamine (polyQ) regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt) with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington's disease (HD). To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt) in Schizosaccharomyces pombe In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S. pombe is uniquely devoid of proteins with more than 10 Q repeats. We found that polyQ Htt forms aggregates within S. pombe cells only with exceedingly long polyQ expansions. Surprisingly, despite the presence of polyQ Htt aggregates in both the cytoplasm and nucleus, no significant growth defect was observed in S. pombe cells. Further, PCR analysis showed that the repetitive polyQ-encoding DNA region remained constant following transformation and after multiple divisions in S. pombe, in contrast to the genetic instability of polyQ DNA sequences in other organisms. These results demonstrate that cells with a low content of polyQ or other aggregation-prone proteins can show a striking resilience with respect to polyQ toxicity and that genetic instability of repetitive DNA sequences may have played an important role in the evolutionary emergence and exclusion of polyQ expansion proteins in different organisms.ImportancePolyglutamine (polyQ) proteins encoded by repetitive CAG DNA sequences serve a variety of normal biological functions. Yet some proteins with abnormally expanded polyQ regions cause neurodegeneration through unknown mechanisms. To study how distinct cellular environments modulate polyQ aggregation and toxicity, we expressed CAG-expanded huntingtin fragments in Schizosaccharomyces pombe In stark contrast to many other eukaryotes, S. pombe is uniquely devoid of proteins containing long polyQ tracts. Our results show that S. pombe cells, despite their low content of endogenous polyQ proteins, exhibit striking and unexpected resilience with respect to polyQ toxicity and that genetic instability of repetitive DNA sequences may have played an important role in the emergence and expansion of polyQ domains in eukaryotic evolution.

Dataset Information

A safe, blood-brain barrier permeable triphenylmethane dye inhibits amyloid-? neurotoxicity by generating nontoxic aggregates.

Publications

A safe, blood-brain barrier permeable triphenylmethane dye inhibits amyloid-β neurotoxicity by generating nontoxic aggregates.

Similar Datasets

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