Abstract
The colocalization of heme rich deposits in the senile plaque of Aβ in the cerebral cortex of the Alzheimer's disease (AD) brain along with altered heme homeostasis and heme deficiency symptoms in AD patients has invoked the association of heme in AD pathology. Heme bound Aβ complexes, depending on the concentration of the complex or peptide to heme ratio, exhibit an equilibrium between a high-spin mono-His bound peroxidase-type active site and a low-spin bis-His bound cytochrome b type active site. The high-spin heme-Aβ complex shows higher peroxidase activity than free heme, where compound I is the reactive oxidant. It is also capable of oxidizing neurotransmitters like serotonin in the presence of peroxide, owing to the formation of compound I. The low-spin bis-His heme-Aβ complex on the other hand shows enhanced peroxidase activity relative to high-spin heme-Aβ. It reacts with H(2)O(2) to produce two stable intermediates, compound 0 and compound I, which are characterized by absorption, EPR and resonance Raman spectroscopy. The stability of compound I of low-spin heme-Aβ is accountable for its enhanced peroxidase activity and oxidation of the neurotransmitter serotonin. The effect of the second sphere Tyr10 residue of Aβ on the formation and stability of the intermediates of low-spin heme-Aβ has also been investigated. The higher stability of compound I for low-spin heme-Aβ is likely due to H-bonding interactions involving Tyr10 in the distal pocket.