PNAS | February 28, 2006 | vol. 103 | no. 9 | 3381-3386
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BIOLOGICAL SCIENCES / NEUROSCIENCE
Amyloid- peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Hani Atamna*, and Kathleen Boyle

Nutrition and Metabolism Center, Children’s Hospital Oakland Research Institute, Oakland, CA 94609

Communicated by Bruce N. Ames, University of California, Berkeley, CA, January 6, 2006 (received for review December 22, 2005)


Amyloid- peptide (A) is the toxic agent in Alzheimer’s disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive A binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H2O2) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that A binding to regulatory heme in vivo is the mechanism by which A causes HD. Heme binds to A, thus preventing A aggregation by forming an A–heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The A–heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of A to heme supports a unifying mechanism by which excessive A induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive A for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.