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Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons

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Molecular and Chemical Neuropathology

Abstract

Considerable evidence suggests that altered neuronal calcium homeostasis plays a role in the neuronal degeneration that occurs in an array of neurological disorders. A reduction in microtubules, the accumulation of 8–15 nm straight filaments, and altered antigenicity toward antibodies to the microtubule-associated protein tau and ubiquitin, as well as granulovacuolar degeneration, are observed in many human neurodegenerative disorders. Progress toward understanding how and why human neurons degenerate has been hindered by the inability to examine living human neurons under controlled conditions. We used cultured human fetal cerebral cortical neurons to examine ultrastructural and antigenic changes resulting from elevations in intracellular calcium levels. Elevation of intracellular calcium by exposure to a calcium ionophore or a reduced level of extracellular Na+ for periods of hours to days caused a loss of microtubules, an increase in 8–15 nm straight filaments, and increased immunostaining with Alz-50 and 5E2 (tau antibodies) and ubiquitin antibodies. Granulovacuolar degeneration was also observed. Antigenic changes in tau were sensitive to phosphatases, and the electrophoretic mobility of tau was altered in cells exposed to calcium ionophore, indicating that tau was excessively phosphorylated as the result of elevated intracellular calcium levels. Colchicine also caused an accumulation of straight filaments and altered tau immunoreactivity, suggesting that a disruption of microtubules secondary to altered calcium homeostasis may be a key event leading to altered tau disposition and neuronal degeneration. These data demonstrate that aberrant rises in intraneuronal calcium levels can result in changes in the neuronal cytoskeleton similar to those seen in neurodegenerative disorders, and suggest that this experimental system will be useful in furthering our understanding of the cellular and molecular mechanisms of human neurological disorders.

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  1. Sanders-Brown Research Center on Aging, and Department of Anatomy & Neurobiology, University of Kentucky Medical Center, 40536-0230, Lexington, KY

    Mark P. Mattson, M. G. Engle & B. Rychlik

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  1. Mark P. Mattson
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  2. M. G. Engle
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  3. B. Rychlik
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Mattson, M.P., Engle, M.G. & Rychlik, B. Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons. Molecular and Chemical Neuropathology 15, 117–142 (1991). https://doi.org/10.1007/BF03159951

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