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Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage

Authors

  • Pei I. Ho,

    1. Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, Massachusetts
    2. Department of Biochemistry, University of Massachusetts, Lowell, Massachusetts
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  • Daniela Ortiz,

    1. Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, Massachusetts
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  • Eugene Rogers,

    1. Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, Massachusetts
    2. Department of Biochemistry, University of Massachusetts, Lowell, Massachusetts
    3. Department of Health and Clinical Sciences, University of Massachusetts, Lowell, Massachusetts
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  • Thomas B. Shea

    Corresponding author
    1. Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, Massachusetts
    2. Department of Biochemistry, University of Massachusetts, Lowell, Massachusetts
    3. Department of Biological Sciences, University of Massachusetts, Lowell, Massachusetts
    • Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, MA 01854
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Abstract

Homocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD). We examined the consequences of treatment of cultured murine cortical neurons with HC. Homocysteine-induced increases in cytosolic calcium, reactive oxygen species, phospho-tau immunoreactivity and externalized phosphatidyl serine (indicative of apoptosis). Homocysteine-induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity, as evidenced by treatment with antagonists of the NMDA channel and metabotropic glutamate receptors, respectively. The NMDA channel antagonist MK-801 reduced tau phosphorylation but not apoptosis after HC treatment, suggesting that HC-mediated apoptosis was not due to calcium influx. Apoptosis after HC treatment was reduced by co-treatment with 3-aminobenazmidine (3ab), an inhibitor of poly-ADP-ribosome polymerase (PARP), consistent with previous reports that ATP depletion by PARP-mediated repair of DNA strand breakage mediated HC-induced apoptosis. Treatment with 3ab did not reduce tau phosphorylation, however, therefore hyperphosphorylation of tau may not contribute to HC-induced apoptosis under these conditions. Inhibition of mitogen-activated protein kinase by co-treatment with the kinase inhibitor PD98059 inhibited tau phosphorylation but not apoptosis after HC treatment. HC accumulation reduces cellular levels of S-adenosyl methionine (SAM); co-treatment with SAM reduced apoptosis, suggesting that inhibition of critical methylation reactions may mediate HC-induced apoptosis. These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes. © 2002 Wiley-Liss, Inc.

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