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Review
. 2013 Sep 10;19(8):823-35.
doi: 10.1089/ars.2012.5027. Epub 2013 Feb 14.

Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression

D Allan Butterfield  1 , Aaron M Swomley, Rukhsana Sultana
Affiliations
Review

Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression

D Allan Butterfield et al. Antioxid Redox Signal. .

Abstract

Significance: Alzheimer disease (AD) is an age-related neurodegenerative disease. AD is characterized by progressive cognitive impairment. One of the main histopathological hallmarks of AD brain is the presence of senile plaques (SPs) and another is elevated oxidative stress. The main component of SPs is amyloid beta-peptide (Aβ) that is derived from the proteolytic cleavage of amyloid precursor protein.

Recent advances: Recent studies are consistent with the notion that methionine present at 35 position of Aβ is critical to Aβ-induced oxidative stress and neurotoxicity. Further, we also discuss the signatures of oxidatively modified brain proteins, identified using redox proteomics approaches, during the progression of AD.

Critical issues: The exact relationships of the specifically oxidatively modified proteins in AD pathogenesis require additional investigation.

Future directions: Further studies are needed to address whether the therapies directed toward brain oxidative stress and oxidatively modified key brain proteins might help delay or prevent the progression of AD.

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Figures

FIG. 1.
FIG. 1.
A general depiction of amyloidogenic processing. Amyloid precursor protein (APP) is cleaved by β-secretase followed by γ-secretase within the bilayer to produce a fragment of amyloid-beta peptide (Aβ), sAPPβ, and AICD. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 2.
FIG. 2.
A general depiction of non-amyloidogenic processing. APP is cleaved by α-secretase followed by γ-secretase within the bilayer to produce a fragment of P3, sAPPα, and APP intracellular domain (AICD). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.
FIG. 3.
FIG. 3.
Amino acid sequence of beta-amyloid peptides. Red color indicates the two additional hydrophobic amino acids that are present in beta-amyloid (1–42), which is critical for higher aggregation rate of beta-amyloid (1–42), and its associated neurotoxicity (please see text for more details). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 4.
FIG. 4.
Schematic illustration of HNE-modified protein. Upon formation of a radical centered allylic carbon on a fatty acid chain, the lipid may interact with molecular O2 that freely diffuses through the bilayer because of its lack of dipole moment, to initiate the lipid peroxidation process that eventually, by way of a proposed Hock cleavage, generates an α/β unsaturated reactive aldehyde [e.g., 4-hydroxy-nonenal (HNE), malondialdehyde, and acrolein]. Membrane-bound proteins may then, by way of nucleophilic side chains such as Cys, Lys, and His, covalently bind the aldehyde that alters the structure and function of the target protein. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 5.
FIG. 5.
Some consequences of elevated ROS and RNS. Reactive oxygen species (ROS) leaked from mitochondria (e.g., O2−•) interact with nitric oxide (NO) produced by nitric oxide synthase (NOS) to produce reactive nitrogen species such as ONOO−, which covalently modify proteins. O2−• can also directly oxidize proteins, lipids, and carbohydrates. O2−• may also be dismutated to H2O2 by superoxide dismutase (SOD) enzymes in an attempt to mitigate O2−• induced damage. However, hydrogen peroxide (H2O2) in the presence of Fe2+ or Cu+ undergoes Fenton chemistry to produce the reactive ROS •OH and −OH, which also cause protein, nucleic acid, and carbohydrate oxidation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 6.
FIG. 6.
A pictorial representation of Aβ oligomerization and insertion into the bilayer. When inserted into the bilayer, Aβ forms an α-helix that allows the peptide backbone carbonyl of Ile-31 to come within Van der Waals distance of the sulfur atom on Met-35, as explained by the i+4 rule of α-helicies. This interaction allows for the formation of a sulfuranyl radical that leads to a catalytic lipid peroxidation process. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 7.
FIG. 7.
A proposed mechanism for the Aβ-induced free radical stress hypothesis. As shown, the electron density surrounding the sulfur atom of Met-35 is pulled away by the more electronegative oxygen of the carbonyl located on the peptide backbone at the position of Ile-31. As discussed, the carbonyl is within Van der Waals distance to the sulfur, which primes the lone pair on the sulfur for one-electron oxidation, forming the sulfuranyl radical. Because this occurs within the bilayer, unsaturated lipids are present, allowing for an allylic hydrogen atom abstraction by the sulfuranyl radical to eventually form a reduced Met-35 that recycles back upon deprotonation to the starting conditions for another cycle. The carbon centered radical may then go on to undergo peroxidation to create reactive aldehydes or may directly interact with another protein or lipid in a radical propagation step. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
FIG. 8.
FIG. 8.
Potential therapeutic targets for AD. There are various potential targets to prevent Alzheimer disease (AD) progression and pathogenesis that include inhibiting the beta-amyloid formation or increasing its clearance from the brain or inhibiting the oxidative stress induced by beta-amyloid peptide. (-) indicates potential targets to combat AD. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
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