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

By A. Abramov, L. Canevari, M. Duchen. 2004

583 citations recorded by the source corpus.

β-Amyloid (βA) 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 βA-induced neuronal death. βA 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 βA-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents βA-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of βA-induced neurodegeneration.

Subfields: Molecular Biology, Physiology, Neuroscience

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. P. Reddy
2. A. Abramov
3. M. Duchen
4. M. Beal
5. A. Scorziello
6. S. Gandhi
7. M. Pekna
8. H. Plun-Favreau

In Physiology

1. P. Reddy
2. M. Beal
3. A. Abramov
4. M. Duchen
5. A. Scorziello
6. S. Gandhi
7. Xiongwei Zhu
8. M. Pekna

In Neuroscience

1. M. Duchen
2. A. Scorziello
3. A. Abramov

Citations in the corpus

• Mitochondria in health and disease: perspectives on a new mitochondrial biology. (2004, methodology): “Cells were protected by provision of GSH precursors (Abramov et al., 2004) or by upregulation of GSH synthesis (Barkats et al.”
• NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases (2021, background): “Consistent with previous study [46], our results showed that the elevation of NOX4 promoted excessive mtROS production in human astrocytes.”
• Astrocyte reactivity and reactive astrogliosis: costs and benefits. (2014, background): “They have been essential for understanding the function of astrocytes in health including their function in metabolism, neurotransmitter recycling, and calcium signaling and to mimic various disease situations such as injury, hypoxia, or neurodegenerative diseases (2, 3, 51, 65, 76, 128, 157, 206, 2”
• Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. (2008, background): “Mitochondrial abnormalities have been found both in neurons and astrocytes [47,54,59], suggesting that both neurons and astrocytes may be damaged by free radicals in the AD brain.”
• PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death (2009, background): “Abnormal calcium homeostasis has been implicated in a range of diseases such as Alzheimer’s disease (Abramov et al., 2003, 2004), Huntington’s disease, amyotrophic lateral sclerosis, and stroke (Mattson, 2007).”
• Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. (2010, background): “[48] reported that Aβ causes a loss of mitochondrial potential in astrocytes but not in neurons.”
• Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, unknown): “Although most deleterious effects of Ab is attributed to Ab deposits (Abramov et al., 2004; Picone et al., 2009), extracellular Ab (i.”
• Three Distinct Mechanisms Generate Oxygen Free Radicals in Neurons and Contribute to Cell Death during Anoxia and Reoxygenation (2007, methodology): “Mixed cultures of hippocampal or cortical neurones and glial cells were prepared as described previously (Abramov et al., 2004) with modifications, from Sprague Dawley rat pups 2– 4 d postpartum (University College London breeding colony).”