Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Abstract

Amyloid-β peptide (Aβ) 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 Aβ 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., H 2 O 2 ) from mitochondria due to the loss of complex IV, which contains heme- a . Now we add more evidence that Aβ binding to regulatory heme in vivo is the mechanism by which Aβ causes HD. Heme binds to Aβ, thus preventing Aβ aggregation by forming an Aβ–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 Aβ–heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H 2 O 2 . Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of Aβ to heme supports a unifying mechanism by which excessive Aβ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive Aβ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.