Cited by 587Alzheimer's disease research and treatmentsMitochondrial Function and PathologyRedox biology and oxidative stress

β-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase

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Abramov, Andrey Y., Canevari, Laura, Duchen, Michael R.·2004·The Journal of Neuroscience

Abstract

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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Crossref · 10.1523/jneurosci.4042-03.2004

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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
Published
2004-01-14
Volume
24
Issue
2
Pages
565-575
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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

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