beta-Amyloid neurotoxicity in human cortical culture is not mediated by excitotoxins.
beta-Amyloid is a metabolic product of the amyloid precursor protein, which accumulates abnormally in senile plaques in the brains of patients with Alzheimer's disease. The neurotoxicity of beta-amyloid has been observed in cell culture and in vivo, but the mechanism of this effect is unclear. In this report, we describe the direct neurotoxicity of beta-amyloid in high-density primary cultures of human fetal cortex. In 36-day-old cortical cultures, beta-amyloid neurotoxicity was not inhibited by the broad-spectrum excitatory amino acid receptor antagonist kynurenate or the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid under conditions that inhibited glutamate and NMDA neurotoxicity. In 8-day-old cortical cultures, neurons were resistant to glutamate and NMDA toxicity but were still susceptible to beta-amyloid neurotoxicity, which was unaffected by excitatory amino acid receptor antagonists. Treatment with beta-amyloid caused chronic neurodegenerative changes, including neuronal clumping and dystrophic neurites, whereas glutamate treatment caused rapid neuronal swelling and neurite fragmentation. These results suggest that beta-amyloid is directly neurotoxic to primary human cortical neurons by a mechanism that does not involve excitatory amino acid receptors.
Department of Neurology, Children's Hospital, Boston, MA 02115.
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J
Busciglio
J
J
Yeh
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BA
Yankner
D000596:Amino Acids / Q000378:metabolism / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017459:Receptors, Amino Acid / Q000378:metabolism
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D017459:Receptors, Amino Acid