Human and rodent amyloid-β peptides differentially bind heme: Relevance to the human susceptibility to Alzheimer's disease

Amyloid-beta (A beta) peptides are implicated in the neurodegeneration of Alzheimer's disease (AD). We previously investigated the mechanism of neurotoxicity of A beta and found that human A beta (huA beta) binds and depletes heme, forming an A beta-heme complex with peroxidase activity. Rodent A beta (roA beta) is identical to huA beta, except for three amino acids within the proposed heme-binding motif (Site-H). We Studied and compared heme-binding between roA beta and huA beta. Unlike roA beta, huA beta binds heme tightly (K-d = 140 +/- 60 nM) and forms a peroxidase. The plot of bound (huA beta-heme) vs. unbound heme fits best to a two site binding hyperbola, suggesting huA beta possesses two heme-binding sites. Consistently. a second high affinity heme-binding site was identified in the lipophilic region (site-L) of huA beta (Kd = 210 +/- 80 nM). The plot of (roA beta-heme) VS. unbound heme, on the other hand, was different as it fits best to a sigmoidal binding Curve, indicating different binding and lower affinity of roA beta for heme (K-d = 1 mu M). The effect of heme-binding to site-H on heme-binding to site-L in roA beta and huA beta is discussed. While both roA beta and huA beta form aggregates equally, rodents lack AD-like neuropathology. High huA beta/heme ratio increases the peroxidase activity. These findings Suggest that depletion of regulatory heme and formation of A beta-heme peroxidase contribute to huA beta's neurotoxicity in the early stages of AD. Phylogenic variations in the amino acid sequence of A beta explain tight heme-binding to huA beta and likely contribute to the increased human Susceptibility to AD. (C) 2009 Elsevier Inc. All rights reserved.