A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.

Hensley, K; Carney, J M; Mattson, M P; Aksenova, M; Harris, M; Wu, J F; Floyd, R A; Butterfield, D A

doi:10.1073/pnas.91.8.3270

Cited by 1,086Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.

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Hensley, K, Carney, J M, Mattson, M P, Aksenova, M, Harris, M, Wu, J F, Floyd, R A, Butterfield, D A·1994·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.91.8.3270PMC PMC43558

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Abstract

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 increases reactive species 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 leakage of electrons from the mitochondrial electron transport chain.
“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
The Results and Discussion report that Aβ peptides generate free radicals and that the Aβ(25–35) fragment produces reactive oxygen species in cell-free experiments. They do not establish increased reactive species in neurons or address the listed NADPH oxidase, Aβ alcohol dehydrogenase, cytochrome oxidase, and mitochondrial electron-leakage mechanisms. No page numbers are available in our copy. (LLM, conf=0.88)
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Self-citation

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.
ORCID: Mattson, M P
Aksenova, M
Butterfield, D A
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
DOI: 10.1073/pnas.91.8.3270
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: Health Sciences › Medicine › Physiology › 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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A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.

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