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Review
. 2007 Sep 1;43(5):658-77.
doi: 10.1016/j.freeradbiomed.2007.05.037. Epub 2007 Jun 13.

Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment

D Allan Butterfield  1 , Tanea Reed, Shelley F Newman, Rukhsana Sultana
Affiliations
Review

Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment

D Allan Butterfield et al. Free Radic Biol Med. .

Abstract

Oxidative stress has been implicated to play a crucial role in the pathogenesis of a number of diseases, including neurodegenerative disorders, cancer, and ischemia, just to name a few. Alzheimer disease (AD) is an age-related neurodegenerative disorder that is recognized as the most common form of dementia. AD is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid beta-peptide (Abeta), and synapse loss. In this review we discuss the role of Abeta in the pathogenesis of AD and also the use of redox proteomics to identify oxidatively modified brain proteins in AD and mild cognitive impairment. In addition, redox proteomics studies in in vivo models of AD centered around human Abeta(1-42) are discussed.

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Figures

Figure 1
Figure 1
Tyrosine nitration. ‘A’ represents reaction of peroxynitrite and carbon dioxide. ‘B’ represents formation of 3-nitrotyrosine.
Figure 1
Figure 1
Tyrosine nitration. ‘A’ represents reaction of peroxynitrite and carbon dioxide. ‘B’ represents formation of 3-nitrotyrosine.
Figure 2
Figure 2
Methionine chemistry. Formation of methione sulfoxide and methionine sulfone.
Figure 3
Figure 3
Aβ(1-42) as a small oligomer is postulated to reside in the lipid bilayer. One-electron oxidation of the S-atom on Met-35, facilitated by the α-helical i + 4 interaction of the backbone carbonyl of Ile-31 with the S-atom of Met-35, forms a positively charged sulfuranyl radical that is stabilized in part by the helical dipole of Aβ(1-42) located in the lipid bilayer. This radical can abstract a lipid acyl allyllic H-atom, forming a lipid carbon radical that immediately binds paramagnetic O2. This peroxyl radical can abstract an allylic H-atom making the lipid hydroperoxide and propagating the chain reaction. The lipid hydroperoxide on arachidonic acid can decompose to HNE, which can subsequently bind to proteins by Michael addition, resulting in oxidative damage to the protein. The SH+ acid on Met has a pKa of minus 5, so loses the H+ easily to reform Met. That is, the reaction is catalytic. This mechanism is consistent with an amplification of damage by a relatively minor degree of conversion of Met to the sulfuranyl free radical of Aβ(1-42).
Figure 4
Figure 4
Diagrammatic representation of redox proteomics.
See this image and copyright information in PMC

References

    1. Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review. Free Radic Res. 2002;36:1307–1313. - PubMed
    1. Butterfield DA, Castegna A, Lauderback CM, Drake J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiol Aging. 2002;23:655–664. - PubMed
    1. Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol Med. 2001;7:548–554. - PubMed
    1. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med. 2002;32:1050–1060. - PubMed
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