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

Soluble oligomers and/or aggregates of Amyloid-beta (A beta) are viewed by many as the principal cause for neurodegeneration in Alzheimer's disease (AD). However, the mechanism by which A beta and its aggregates cause neurodegeneration is not clear. The toxicity of A beta 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 A beta's hydrophobicity. In order to understand the role of A beta in these cytopathologies we hypothesized that A beta impairs specific metabolic pathways. We focused on heme metabolism because it links iron, mitochondria, and A beta. We generated experimental evidence showing that A beta alters heme metabolism in neuronal cells. Furthermore, we demonstrated that A beta binds to and depletes intracellular regulatory heme (forming an A beta-heme complex), which provides a strong molecular connection between A beta 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. A beta-heme exhibits a peroxidase-like catalytic activity, which catalytically accelerates oxidative damage. Interestingly, the amino acids sequence of rodent A beta (roA beta) and human A beta (huA beta) is identical except for three amino acids within the hydrophilic region, which is also the heme-binding motif that we identified. We found that huA beta, unlike roA beta, binds heme tightly and forms a peroxidase. Although, roA beta and huA beta 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 huA beta'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.