Amyloid-β Peptide Binds with Heme to Form a Peroxidase: Relationship to the Cytopathologies of Alzheimer's Disease

Amyloid-β peptide (Aβ) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive Aβ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologie...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (9), p.3381-3386
Main Authors: Atamna, Hani, Boyle, Kathleen
Format: Article
Language:English
Subjects:
Aggregation
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Amino acids
Amyloid beta-Peptides - metabolism
Binding sites
Biological Sciences
Biology
Brain damage
Cell aggregates
Cell Line, Tumor
Fluorescence
Heme - metabolism
Humans
Iron - metabolism
Mitochondria
Monomers
Neuroblastoma
Neurology
Neurons
Neurotransmitters
Oxidation
Oxidation-Reduction - drug effects
Peptide Fragments - pharmacology
Peptides
Peroxidases - chemistry
Peroxidases - metabolism
Protein Binding
Spectrum Analysis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Amyloid-β peptide (Aβ) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive Aβ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H₂O₂) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that Aβ binding to regulatory heme in vivo is the mechanism by which Aβ causes HD. Heme binds to Aβ, thus preventing Aβ aggregation by forming an Aβ-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The Aβ-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H₂O₂. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of Aβ to heme supports a unifying mechanism by which excessive Aβ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive Aβ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0600134103