Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Abstract

Abstract. The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-β (Aβ) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Aβ. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of Aβ species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Aβ. The potential significance of combining MB and osmolytes to treat AD are discussed.

Oxidation Inhibits Iron-Induced Blood Coagulation

“…As in the case of the health benefits achieved by ingestion of salicylates (aspirin), hydrogen peroxide may act by eliminating harmful hydroxyl radicals from the circulating blood. The effect of methylene blue on the non-enzymatic polymerization of fibrinogen molecules was less pronounced than that of hydrogen peroxide, possibly due to its weaker oxidation power [20]. The inhibition of fibrinogen polymerization by sodium selenite demonstrated in this paper may occur by oxidation of hydroxyl radicals and the concomitant reduction of Se 4+ to Se 2+ .…”

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

“…It also exhibits potent antioxidant effects in mitochondria due to its redox property. The cycling between reduced (MBH2) and oxidized (MB) forms facilitates electron transfer, thus preventing electron leakage, increasing mitochondrial oxidative phosphorylation, and reducing ROS overproduction under pathological conditions (Atamna & Kumar, 2010). Based on these previous studies, we examined whether the treatment with MB could alleviate dysfunctional mitochondria and delay premature senescence associated with HGPS cells.…”

“…In addition, we find that MB treatment improves HGPS heterochromatin organization and corrects the expression of more than 50% of the misregulated genes in the HGPS nucleus (Figs 5E–G and 6). As a highly permeable molecule, it is known that MB can potentially enter all the other cellular compartments, including the nucleus (Kelner et al ., 1988; Atamna & Kumar, 2010; Oz et al ., 2011). Thus, the results in the nucleus were encouraging but not completely unexpected.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Methylene blue can enhance cytochrome c oxidase activity through direct electron donation [80,81]. In a preclinical AD mouse model, methylene blue treatment reduced Tau-neurofibrillary tangle burden [82]. Clinical investigations of methylene blue as a treatment for AD have not been conducted.…”