Hemoglobin binding to A beta and HBG2 SNP association suggest a role in Alzheimer's disease

Abstract

From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to A beta1-42. We showed the oxidized form of adult Hb (metHb A) binds with greater affinity to A beta1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C-->T) at -158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with A beta and may protect against the development of AD.

Figure 1

Positive controls (1M APOE4 and 7nM anti-amyloid monoclonal antibody) and negative controls (1M monoclonal antibody SMI-31 and 1M BSA). Data shown is corrected for bulk effects by subtracting the response observed in fc1 from that observed in fc2.

Figure 2

Data shown is corrected for bulk effects by subtracting the response observed in fc1 from that observed in fc2. Binding of the amyloid peptide (Aβ1-42) appears to be mediated by the redox state of the heme iron. Globin without a heme group or hemoglobin where the heme iron is oxidized to Fe⁺³ (metHb) is permissive for binding. In contrast, when the heme iron is in the Fe⁺² reduced state (oxyHb), binding is blocked.