Affiliations: Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute (CHORI), Oakland, CA 94609, USA | Program of Cognitive Neuroscience, Department of Psychology, Babeş-Bolyai University, Cluj-Napoca, CJ, Romania
Correspondence:
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Address for correspondence: Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute (CHORI), 5700 Martin Luther King Jr. Way, Oakland, CA, 94609-1673, USA. Tel.: +1 510 450 7934; Fax: +1 510 450 7910; E-mail: [email protected].
Abstract: Genetic, biochemical, and immunological evidences support a mechanistic role for amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer's disease (AD). Aβ 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 Aβ 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 β and heme required to support this hypothesis was demonstrated by our discovery that heme binds with Aβ, forming a complex (Aβ-heme). Heme prevented the aggregation of Aβ by forming Aβ-heme, suggesting Aβ-heme may prevent Aβ aggregation in vivo. The downside, however, is that Aβ-heme is a peroxidase, which if not regulated might indiscriminately oxidize diverse biomolecules. Additionally, excessive production of Aβ 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 Aβ-induced heme-deficiency leading to mitochondrial dysfunction, Aβ-heme peroxidase, and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD.
