Hemoglobin binding to Aβ 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 Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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.

Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes

“…Genes unique to this category (Fig. 3E) regulate inflammation such as leucine-rich repeat-containing-18 (LRRC18, FC=104.5) and hemoglobin subunit gamma-2 (HBG2, FC=8.9 (52, 53)); as well as lymphocyte proliferation and differentiation including SH2B adaptor-3 (SH2B3, FC=2.0 (54)) and killer cell lectin-like receptor subfamily-G1 (KLRG1, FC=2.4 (55)).…”

ABCG2 reduces ROS‐mediated toxicity and inflammation: a potential role in Alzheimer’s disease

“…Hemoglobin was shown to bind Aβ, promote Aβ oligomer formation and localize in Aβ deposits and neurons (Wu et al. 2004; Perry et al. 2008).…”

“…Heme is an important part of the hemoglobin for its function to deliver oxygen to tissues. Hemoglobin was shown to bind Ab, promote Ab oligomer formation and localize in Ab deposits and neurons (Wu et al 2004;Perry et al 2008). Heme can also bind to Ab forming an Ab-heme complex.…”

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

“…Several lines of experimental evidence provided support that heme metabolism may be a specific metabolic pathway that is targeted by Aβ peptides [26,[53][54][55]. We recently showed a specific heme-binding motif in human Aβ peptides [26].…”