Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity.
Although the accumulation of the neurotoxic peptide beta amyloid (betaA) in the CNS is a hallmark of Alzheimer's disease, the mechanism of betaA neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide betaA (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, approximately 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 betaA, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support.
Abramov
Andrey Y
AY
Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom.
Canevari
Laura
L
Duchen
Michael R
MR
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000682:Amyloid / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology; D018920:Coculture Techniques; D005110:Extracellular Space; D005978:Glutathione / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D007424:Intracellular Fluid / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000494:pharmacology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D007464:Clioquinol; D005978:Glutathione; D015032:Zinc; D002118:Calcium