Abstract
Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.
Highlights
In JNPL3 organotypic brain slices[10]
Inhibitors of Tau aggregation are being considered as therapeutic interventions against Alzheimer disease (AD), and methylene blue disaggregates Tau NFTs3
Several studies have demonstrated the ability of methylene blue to prevent Tau aggregation in transgenic mouse models expressing the P301L or P301S Tau mutations associated with the formation of neurofibrillary tangles (NFTs) in mice and in human disease
Summary
In JNPL3 organotypic brain slices[10]. methylene blue improved behavioral deficits and Tau pathology in C. elegans and Drosophila models[11,12]. Methylene blue, and its mono and di-N-demethylated forms, azure B and azure A, were shown to interact with and promote the oxidation of Tau cysteine residues, retaining Tau in a monomeric conformation, preventing formation of fibrils and their toxic precursors[14,15] The identification of this mechanism prompted us to ask whether methylene blue may modulate the activity of caspases, a group of cysteinyl proteases involved in inflammation and cell death. Our results showed that methylene blue and its derivatives efficiently inhibited active caspases in vitro, in cells, and in vivo at concentrations allowing phenothiazine-mediated Tau disaggregation These results indicate that methylene blue or its derivatives could (1) have an additional effect in AD by inhibiting caspases, (2) be used as a drug to prevent caspase activation in other degenerative conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of effector Casp[3]
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