Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons.
In several neurological disorders including Alzheimer's disease, abnormal accumulations of cytoskeleton-associated proteins manifest as neurofibrillary tangles (NFTs) in vulnerable brain regions. Antibodies recognizing tau (5E2 and Alz-50) and ubiquitin epitopes in NFTs were used to examine the influence of glutamate and Ca2+ influx on antigen expression in cultured rat hippocampal neurons. Glutamate caused the degeneration of a subpopulation of pyramidal neurons, which exhibited increased immunostaining with all three antibodies. Subtoxic levels of glutamate also increased 5E2 and Alz-50 antigen levels in a subpopulation of neurons, particularly in the distal regions of the axons. Both glutamate-induced degeneration and increases in tau and ubiquitin immunostaining were prevented by removal of extracellular Ca2+. Increased immunostaining was also induced by Ca2+ ionophore A23187 or elevated levels of extracellular K+. The antigenic changes occurred within 1 hr of exposure to glutamate or A23187 and were not prevented by the protein synthesis inhibitor cycloheximide. These data indicate that Ca2+ influx caused by glutamate can lead to modifications of extant proteins similar to those seen in NFTs.
Sanders-Brown Research Center on Aging, University of Kentucky Medical Center, Lexington 40536-0230.
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Mattson
D000818:Animals; D000941:Antigens / Q000276:immunology; D002118:Calcium / Q000494:pharmacology*; D002478:Cells, Cultured; D000939:Epitopes; D005971:Glutamates / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D008869:Microtubule-Associated Proteins / Q000276:immunology; D009410:Nerve Degeneration; D009454:Neurofibrils / Q000276:immunology*; D009474:Neurons / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D013194:Staining and Labeling; D014452:Ubiquitins / Q000276:immunology; D016875:tau Proteins
D000941:Antigens; D000939:Epitopes; D005971:Glutamates; D008869:Microtubule-Associated Proteins; D014452:Ubiquitins; D016875:tau Proteins; D002118:Calcium