Hemoglobin binding to A beta and HBG2 SNP association suggest a role in Alzheimer's disease.
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.
Perry
Rodney T
RT
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. rperry@uab.edu
Gearhart
Debra A
DA
Wiener
Howard W
HW
Harrell
Lindy E
LE
Barton
James C
JC
Kutlar
Abdullah
A
Kutlar
Ferdane
F
Ozcan
Ozan
O
Go
Rodney C P
RC
Hill
William D
WD
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics; D015252:Deoxyribonucleases, Type II Site-Specific; D005192:Family Health; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D020349:Surface Plasmon Resonance / Q000379:methods
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D006454:Hemoglobins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016222:Fibroblast Growth Factor 2; C028649:endodeoxyribonuclease XmnI; D015252:Deoxyribonucleases, Type II Site-Specific