Changes in Intracellular Calcium and Glutathione in Astrocytes as the Primary Mechanism of Amyloid Neurotoxicity
Open accessAbstract
Although the accumulation of the neurotoxic peptide β amyloid (βA) in the CNS is a hallmark of Alzheimer's disease, the mechanism of βA neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide βA (1–42) and the neurotoxic fragment (25–35) caused sporadic cytoplasmic calcium [intracellular calcium ([Ca 2+]c)] signals in astrocytes that continued for hours, whereas adjacent neurons were completely unaffected. Nevertheless, after 24 hr, although astrocyte cell death was marginally increased, ∼50% of the neurons had died. The [Ca 2+]c signal was entirely dependent on Ca 2+influx and was blocked by zinc and by clioquinol, a heavy-metal chelator that is neuroprotective in models of Alzheimer's disease. Neuronal death was associated with Ca 2+-dependent glutathione depletion in both astrocytes and neurons. Thus, astrocytes appear to be the primary target of βA, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support.
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These astrocytic abnormalities could be due to direct action of Aβ on astrocytes and enhanced receptor-mediated Ca2+ signaling, and are likely to affect the neuronal network by extending areas of functional alteration and abnormal synchronization.
“These abnormalities could be due to a direct action of Aβ on astrocytes 113 as well as enhanced receptor-mediated Ca 2+ signaling (see above) and are likely to affect the neuronal network, e.g. by extending the areas of functional alteration and abnormal synchronization.”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [113]
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References 43 · Cited by 337
- Authors
- Abramov, A. Y., Canevari, L., & Duchen, M. R.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-06-15
- Volume
- 23
- Issue
- 12
- Pages
- 5088-5095
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6741151
- OpenAlex
- W2152093646
- Cited by
- 337
- References
- 43
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 14 · 2021: 11 · 2020: 12 · 2019: 15 · 2018: 14 · 2017: 14 · 2016: 20 · 2015: 24 · 2014: 20 · 2013: 22 · 2012: 23
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Royal Society
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amyloid-beta, amyloid neurotoxicity, Alzheimer's disease, astrocytes, intracellular calcium, glutathione depletion, calcium influx, zinc, clioquinol, neuronal cell death, astrocyte-neuron interaction
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Astrocytes, Calcium, Cell Survival, Cells, Cultured, Chelating Agents, Extracellular Space, Glutathione, Hippocampus, Intracellular Fluid, Clioquinol, Neurons, Peptide Fragments, Zinc, Amyloid beta-Peptides, Rats, Sprague-Dawley, Neuroprotective Agents, Coculture Techniques, Calcium Signaling, Rats
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