P3-366: The complexation of amyloid-β with heme forms a peroxidase: Mechanism of neurotoxicity in Alzheimer’s disease

Abstract

The molecular mechanism by which Amyloid–β (Aβ) peptide causes the neurodegeneration in Alzheimer's disease (AD) is not known. We previously proposed that excessive Aβ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD including mitochondrial dysfunction, loss of complex IV, iron accumulation, and oxidative stress (Atamna et al. 2004, PNAS). In the current study we searched for additional evidence that Ab binding to regulatory heme is the mechanism by which Aβ causes HD. The experiments included techniques of tissue culture, biochemistry, radiobiology, and HPLC. We found that heme binds to Aβ forming an Aβ–heme complex. We also found that Aβ induces heme synthesis and iron uptake in human neuroblastoma cells, which provides strong support that Aβ triggers HD. Interestingly, we also found that the Aβ–heme complex is a peroxidase, which catalyzes the oxidation of serotonin and DOPA by H2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits the Aβ–heme peroxidase. The binding of Aβ to heme supports a unifying mechanism by which elevated levels of Aβ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the depletion of regulatory heme by excessive Aβ and Aβ–heme peroxidase to mitochondrial dysfunction, oxidative stress, neurotoxicity and other cytopathologies of AD will be discussed.