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The Journal of Neuroscience, August 15, 1999, 19(16):7100-7110

Truncated Apolipoprotein E (ApoE) Causes Increased Intracellular Calcium and May Mediate ApoE Neurotoxicity

Martin Tolar¹, Jeffrey N. Keller², Stephen Chan², Mark P. Mattson², Marcos A. Marques³, and Keith A. Crutcher^{1, 3}

¹ Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, ² Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, and ³ ApoLogic, Inc., Cincinnati, Ohio 45219

Apolipoprotein E (apoE)-related synthetic peptides, the 22 kDa N-terminal thrombin-cleavage fragment of apoE (truncated apoE), and full-length apoE have all been shown to exhibit neurotoxic activity under certain culture conditions. In the present study, protease inhibitors reduced the neurotoxicity and proteolysis of full-length apoE but did not block the toxicity of truncated apoE or a synthetic apoE peptide, suggesting that fragments of apoE may account for its toxicity. Additional experiments demonstrated that both truncated apoE and the apoE peptide elicit an increase in intracellular calcium levels and subsequent death of embryonic rat hippocampal neurons in culture. Similar effects on calcium were found when the apoE peptide was applied to chick sympathetic neurons. The rise in intracellular calcium and the hippocampal cell death caused by the apoE peptide were significantly reduced by receptor-associated protein, removal of extracellular calcium, or administration of the specific NMDA glutamate receptor antagonist MK-801. These results suggest that apoE may be a source of both neurotoxicity and calcium influx that involves cell surface receptors. Such findings strengthen the hypothesis that apoE plays a direct role in the pathology of Alzheimer's disease.

Key words: proteolysis; intracellular calcium; apolipoprotein E; neurotoxicity; LRP; degeneration; Alzheimer's disease

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19167100-11$05.00/0

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