Amino acids variations in Amyloid-β peptides, mitochondrial dysfunction, and new therapies for Alzheimer’s disease

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Soluble oligomers and/or aggregates of Amyloid-beta (Abeta) are viewed by many as the principal cause for neurodegeneration in Alzheimer's disease (AD). However, the mechanism by which Abeta and its aggregates cause neurodegeneration is not clear. The toxicity of Abeta has been attributed to its hydrophobicity. However, many specific mitochondrial cytopathologies e.g., loss of complex IV, loss of iron homeostasis, or oxidative damage cannot be explained by Abeta's hydrophobicity. In order to understand the role of Abeta in these cytopathologies we hypothesized that Abeta impairs specific metabolic pathways. We focused on heme metabolism because it links iron, mitochondria, and Abeta. We generated experimental evidence showing that Abeta alters heme metabolism in neuronal cells. Furthermore, we demonstrated that Abeta binds to and depletes intracellular regulatory heme (forming an Abeta-heme complex), which provides a strong molecular connection between Abeta and heme metabolism. We showed that heme depletion leads to key cytopathologies identical to those seen in AD including loss of iron homeostasis and loss of mitochondrial complex IV. Abeta-heme exhibits a peroxidase-like catalytic activity, which catalytically accelerates oxidative damage. Interestingly, the amino acids sequence of rodent Abeta (roAbeta) and human Abeta (huAbeta) is identical except for three amino acids within the hydrophilic region, which is also the heme-binding motif that we identified. We found that huAbeta, unlike roAbeta, binds heme tightly and forms a peroxidase. Although, roAbeta and huAbeta equally form fibrils and aggregates, rodents do not develop AD-like neuropathology. These findings led us to propose a new mechanism for mitochondrial dysfunction and huAbeta's neurotoxicity. This mechanism prompted the development of methylene blue (MB), which increased heme synthesis, complex IV, and mitochondrial function. Thus, MB may delay the onset and progression of AD and serve as a lead to develop novel drugs to treat AD.