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

Neurobiol Aging. 2008 Feb;29(2):185-93. doi: 10.1016/j.neurobiolaging.2006.10.017. Epub 2006 Dec 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Apolipoprotein E4 / genetics
  • Deoxyribonucleases, Type II Site-Specific
  • Family Health
  • Female
  • Fibroblast Growth Factor 2 / genetics*
  • Fibroblast Growth Factor 2 / metabolism*
  • Hemoglobins / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Peptide Fragments / metabolism*
  • Polymorphism, Genetic*
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Surface Plasmon Resonance / methods


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Hemoglobins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Fibroblast Growth Factor 2
  • endodeoxyribonuclease XmnI
  • Deoxyribonucleases, Type II Site-Specific