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The Journal of Neuroscience, June 15, 2003, 23(12):5088-5095

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Changes in Intracellular Calcium and Glutathione in Astrocytes as the Primary Mechanism of Amyloid Neurotoxicity

Andrey Y. Abramov,1 Laura Canevari,2 and Michael R. Duchen1

1Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom, and 2Miriam Marks Division of Neurochemistry, Institute of Neurology, London WC1N 3BG, United Kingdom

Although the accumulation of the neurotoxic peptide {beta} amyloid ({beta}A) in the CNS is a hallmark of Alzheimer's disease, the mechanism of {beta}A neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide {beta}A (1–42) and the neurotoxic fragment (25–35) caused sporadic cytoplasmic calcium [intracellular calcium ([Ca2+]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 [Ca2+]c signal was entirely dependent on Ca2+ 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 Ca2+-dependent glutathione depletion in both astrocytes and neurons. Thus, astrocytes appear to be the primary target of {beta}A, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support.

Key words: {beta}-amyloid; intracellular calcium; astrocyte; neuron; Alzheimer; glutathione

Received Feb. 12, 2003; revised Apr. 4, 2003; accepted Apr. 10, 2003.




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