Abstract
Methylene blue (MB) inhibits the aggregation of tau, a main constituent of neurofibrillary tangles. However, MB’s mode of action in vivo is not fully understood. MB treatment reduced the amount of sarkosyl-insoluble tau in Drosophila that express human wild-type tau. MB concurrently ameliorated the climbing deficits of transgenic tau flies to a limited extent and diminished the climbing activity of wild-type flies. MB also decreased the survival rate of wild-type flies. Based on its photosensitive efficacies, we surmised that singlet oxygen generated through MB under light might contribute to both the beneficial and toxic effects of MB in vivo. We identified rose bengal (RB) that suppressed tau accumulation and ameliorated the behavioral deficits to a lesser extent than MB. Unlike MB, RB did not reduce the survival rate of flies. Our findings indicate that singlet oxygen generators with little toxicity may be suitable drug candidates for treating tauopathies.
Highlights
MB reportedly prevents tau-related neurotoxicity in P301S transgenic mice by upregulating the antioxidant response pathway through NF-E2-related factor 2 (Nrf2/ARE)[10]
In search of a compound that has a common efficacy as MB on tau, but with a better safety profile, we investigated the effects of rose bengal (RB)
Aggregated tau proteins become insoluble in the detergent sarkosyl[25], and can be reasonably used as a proxy measure of “pathology.” In the present study, we successfully detected tau accumulation in sarkosyl-insoluble fractions extracted from the heads of flies that express human wild-type tau
Summary
MB reportedly prevents tau-related neurotoxicity in P301S transgenic mice by upregulating the antioxidant response pathway through NF-E2-related factor 2 (Nrf2/ARE)[10]. The lack of an effect at a high-dose MB was assumed to be indirect, partially due to limitation in the ability to absorb MB, depending on its redox state, in stomach in the presence of food[18] Taken together, these results suggest the role of oxidizing property of MB with regard to its perplexing impacts. Transgenic proteins expressed in all fly neurons can induce neurotoxicity; those flies can be used as a model to assess the effects of drugs on protein accumulation and their phenotypes. Another advantage of using Drosophila is that we are able to evaluate the toxicity of drug treatment in vivo by analyzing mortality and behaviors
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