Heme binding to Amyloid-beta peptide: mechanistic role in Alzheimer's disease.
Genetic, biochemical, and immunological evidences support a mechanistic role for amyloid-beta (Abeta) peptide in the pathophysiology of Alzheimer's disease (AD). Abeta appears to trigger most of the disparate cytopathologies of AD (e.g. loss of iron homeostasis and mitochondrial complex IV), which may initiate synaptic dysfunction, hypometabolism, and memory loss. However, the molecular mechanism that links Abeta to the neurodegeneration of AD is not clear. We have provided evidence for heme's key role in the important cytopathologies of AD, hypothesizing a functional deficiency for heme in the brains of AD patients. The molecular link between beta and heme required to support this hypothesis was demonstrated by our discovery that heme binds with Abeta, forming a complex (Abeta-heme). Heme prevented the aggregation of Abeta by forming Abeta-heme, suggesting Abeta-heme may prevent Abeta aggregation in vivo. The downside, however, is that Abeta-heme is a peroxidase, which if not regulated might indiscriminately oxidize diverse biomolecules. Additionally, excessive production of Abeta in AD brain may bind to and restrict the bioavailability of regulatory heme, creating a condition of heme-deficiency. Regulatory heme regulates heme synthesis, iron homeostasis, specific signaling pathways, and intermediary metabolism. A novel model of Abeta-induced heme-deficiency leading to mitochondrial dysfunction, Abeta-heme peroxidase, and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD.
Atamna
Hani
H
Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute (CHORI), Oakland, CA 94609, USA. hatamna@chori.org
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001667:Binding, Competitive / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D006418:Heme; D003300:Copper; D002784:Cholesterol; D007501:Iron; D015032:Zinc