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

Rodney T. Perry, Debra A. Gearhart, Howard W. Wiener, Lindy E. Harrell, James C. Barton, Abdullah Kutlar, Ferdane Kutlar, Ozan Ozcan, Rodney C.P. Go, William D Hill

Research output: Contribution to journalArticle

17 Scopus citations

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 Aβ1-42. We showed the oxidized form of adult Hb (metHb A) binds with greater affinity to Aβ1-42 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 Aβ and may protect against the development of AD.

Original languageEnglish (US)
Pages (from-to)185-193
Number of pages9
JournalNeurobiology of Aging
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • Amyloid
  • Fetal hemoglobin
  • Gamma globin
  • Heme
  • Methemoglobin
  • Neurological
  • Polymorphism
  • Vascular disease

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    Perry, R. T., Gearhart, D. A., Wiener, H. W., Harrell, L. E., Barton, J. C., Kutlar, A., Kutlar, F., Ozcan, O., Go, R. C. P., & Hill, W. D. (2008). Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease. Neurobiology of Aging, 29(2), 185-193. https://doi.org/10.1016/j.neurobiolaging.2006.10.017