β-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase
Open accessAbstract
Beta-amyloid (betaA) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of betaA-induced neuronal death. betaA causes a loss of mitochondrial potential in astrocytes but not in neurons. The mitochondrial response consists of Ca2+-dependent transient depolarizations superimposed on a slow collapse of potential. The slow response is both prevented by antioxidants and, remarkably, reversed by provision of glutamate and other mitochondrial substrates to complexes I and II. These findings suggest that the depolarization reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. Inhibition of NADPH oxidase by diphenylene iodonium or 4-hydroxy-3-methoxy-acetophenone blocks betaA-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents betaA-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of betaA-induced neurodegeneration.
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Astrocytes are associated with oxidative stress by Aβ-induced ROS production.
“Astrocytes are associated with oxidative stress by Aβ-induced ROS production [46].”
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- Authors
- Abramov, A. Y., Canevari, L., & Duchen, M. R.
- Affiliations
- University College London (GB)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Duchen, Michael R.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-01-14
- Volume
- 24
- Issue
- 2
- Pages
- 565-575
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729998
- OpenAlex
- W2140616438
- Cited by
- 587
- References
- 41
- Citations by year
- 2026: 24 · 2025: 13 · 2024: 23 · 2023: 25 · 2022: 25 · 2021: 32 · 2020: 25 · 2019: 27 · 2018: 26 · 2017: 26 · 2016: 36 · 2015: 19 · 2014: 42 · 2013: 35 · 2012: 27
- FWCI
- 19.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- amyloid-beta, Alzheimer's disease, NADPH oxidase, astrocytes, neuronal cell death, mitochondrial depolarization, oxidative stress, reactive oxygen species, glutathione depletion, mitochondrial complex I, succinate dehydrogenase, glutamate, diphenyleneiodonium, neurodegeneration
- MeSH terms
- Mitochondrial Permeability Transition Pore, Animals, Astrocytes, Calcium, Cells, Cultured, Enzyme Activation, Glutathione, Ion Channels, Membrane Potentials, Mitochondria, Neurons, Peptide Fragments, Amyloid beta-Peptides, Cell Death, Rats, Sprague-Dawley, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Mitochondrial Membrane Transport Proteins, Rats
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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