Susceptibility of Amyloid β Peptide Degrading Enzymes to Oxidative Damage: A Potential Alzheimer's Disease Spiral
Abstract
Insulysin (IDE) and neprilysin (NEP) were found to be inactivated by oxidation with hydrogen peroxide, an iron-ascorbate oxidation system, and by treatment with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). In each case reaction led to the introduction of protein carbonyl groups as judged by reaction with 2,4-dintrophenylhydrazine. IDE was inactivated by reaction with 4-hydroxy-2-nonenal (HNE) with the concomitant formation of protein adducts. NEP was not inactivated to a significant extent by HNE, but some HNE-adduct formation did occur. Prior reaction with hydrogen peroxide or AAPH led to enhanced formation of HNE adducts. Treatment of IDE with AAHP or hydrogen peroxide increased its susceptibility to proteolysis, while treatment of NEP with iron/ascorbate or hydrogen peroxide increased its susceptibility to proteolysis. Since IDE and NEP play a prominent role in the clearance of amyloid beta peptides, their oxidative inactivation and enhanced proteolysis can contribute to the onset and/or progression of Alzheimer's disease.
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Oxidative stress may contribute to Aβ accumulation by inactivating Aβ-degrading enzymes.
“Oxidative stress may also contribute to Aβ accumulation by inactivating Aβ-degrading enzymes”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Shinall et al., 2005
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McManus, M. J., Murphy, M. P., & Franklin, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0552-11.2011 · Cited by 432 · see citing works
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Saido, T., & Leissring, M. A. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006379 · Cited by 368 · see citing works
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Love, S., & Miners, J. S. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1522-0 · Cited by 299 · see citing works
Insulin-Degrading Enzyme in the Fight against Alzheimer's Disease
Kurochkin, I. V., Guarnera, E., & Berezovsky, I. N. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.10.008 · Cited by 185 · see citing works
- Authors
- Shinall, H., Song, E. S., & Hersh, L. B.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Hersh, Louis B.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-10-18
- Volume
- 44
- Issue
- 46
- Pages
- 15345-15350
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2043530890
- Cited by
- 94
- References
- 0
- Citations by year
- 2024: 1 · 2023: 1 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 5 · 2015: 8 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R21AG024899, AG024899)
- National Institute on Drug Abuse (DA02243, R01DA002243)
- National Institute of Neurological Disorders and Stroke (R01NS046517, NS046517)
- National Center for Research Resources (P20 RR02017)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- neprilysin, amyloid-beta, oxidative inactivation, protein carbonylation, 4-hydroxynonenal, protein adducts, hydrogen peroxide, AAPH, proteolysis, Alzheimer's disease, amyloid clearance
- MeSH terms
- Aldehydes, Alzheimer Disease, Amidines, Ascorbic Acid, Chlorides, Chymotrypsin, Ferric Compounds, Hydrogen Peroxide, Insulysin, Oxidation-Reduction, Trypsin, Neprilysin, Amyloid beta-Peptides
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