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A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.
Open accessAbstract
beta-Amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggregates to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain the mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that beta-amyloid, in aqueous solution, fragments and generates free radical peptides. beta-Amyloid fragments, at concentrations that previously have been shown to be neurotoxic to cultured neurons, can inactivate oxidation-sensitive glutamine synthetase and creatine kinase enzymes. Also, salicylate hydroxylation assays indicate that reactive oxygen species are generated by the beta-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease.
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“Aβ is reported to increase RS in neurons via multiple mechanisms, including direct Aβ-induced RS production, elevated NADPH oxidase activity, interaction with mitochondria-associated Aβ alcohol dehydrogenase, inhibition of cytochrome oxidase (respiratory complex IV), and by causing leakage of electrons from the mitochondrial electron transport chain (Hensley et al., 1994; Canevari et al., 1999; L”
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 Hensley et al., 1994
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Metadata
- Authors
- Hensley, K., Carney, J. M., Mattson, M. P., Aksenova, M., Harris, M., Wu, J. F., Floyd, R. A., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- Department of Chemistry, University of Kentucky, Lexington 40506.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1994-04-12
- Volume
- 91
- Issue
- 8
- Pages
- 3270-3274
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC43558
- OpenAlex
- W2070117026
- Cited by
- 1,086
- References
- 23
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 20 · 2023: 16 · 2022: 21 · 2021: 26 · 2020: 15 · 2019: 18 · 2018: 26 · 2017: 15 · 2016: 23 · 2015: 27 · 2014: 26 · 2013: 32 · 2012: 34
- FWCI
- 35.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (9108764)
- Glenn Foundation for Medical Research
- Fondation pour la Recherche Médicale
- National Institutes of Health (AG-10836)
- National Institute on Aging (AG 09690, P01AG010836, R01AG009690, AG 10836)
- Office of Naval Research
- National Institute of Neurological Disorders and Stroke (R01NS023307, NS-23307)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- amyloid-beta, amyloid fibril formation, neurotoxicity, free radicals, reactive oxygen species, glutamine synthetase, creatine kinase, salicylate hydroxylation, amyloid plaques, Alzheimer's disease, peptide fragmentation, membrane alterations
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Chromatography, High Pressure Liquid, Electron Spin Resonance Spectroscopy, Free Radicals, Gas Chromatography-Mass Spectrometry, Molecular Sequence Data, Neurotoxins, Salicylates, Amyloid beta-Peptides
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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