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βAPP Metabolites, Radicals, Calcium, and Neurodegeneration: Novel Neuroprotective Strategies

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Neurodegenerative Diseases

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Abstract

Many biochemical and molecular alterations in the brains of victims of Alzheimer’s disease (AD) and other age-associated neurodegenerative disorders have been described. Unfortunately, it remains unclear which of the alterations contribute to the neuronal damage, which represent compensatory and cytoprotective responses to ongoing cell injury, and which are mere remnants of damaged cells in general. The present article describes studies that have been performed in our laboratories to help define roles for two major metabolites of the β-amyloid precursor protein (βAPP) in the pathogenesis of AD. In addition, we discuss findings concerning age-related alterations in brain metabolism (e.g., reduced glucose availability), and cellular signaling systems regulating neuronal plasticity and survival (e.g., neurotrophic factors), that are likely to impact on the biological activities of βAPP metabolites. Cellular systems regulating metabolism of calcium and reactive oxygen species (ROS) appear to be critical targets of both neurodegenerative and neuroprotective pathways. We therefore highlight the variety of both natural and synthetic compounds that can stabilize calcium homeostasis and ROS metabolism, and which may thus prove effective in reducing neuronal injury in a variety of neurodegenerative disorders. We emphasize βAPP in this chapter, not because it is the only determinant of AD, but rather because increasing data suggest it plays a pivotal role in many cases. This article is not intended to be a comprehensive review of the literature, and we refer the reader to review articles that provide more in-depth analyses of our current understanding of the molecular and cellular pathophysiology of AD1–4.

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Authors and Affiliations

  1. Sanders-Brown Research Center on Aging, University of Kentucky, Lexington, KY, 40536, USA

    Mark P. Mattson, Steven W. Barger, Katsutoshi Furukawa, Robert J. Mark, Virginia L. Smith-Swintosky & Annadora J. Bruce

  2. Departments of Anatomy & Neurobiology, University of Kentucky, Lexington, KY, 40536, USA

    Mark P. Mattson & Robert J. Mark

  3. Department of Neurology, University of Kentucky, Lexington, KY, 40536, USA

    L. Creed Pettigrew

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  1. Mark P. Mattson
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  2. Steven W. Barger
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  3. Katsutoshi Furukawa
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  4. Robert J. Mark
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  5. Virginia L. Smith-Swintosky
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  6. L. Creed Pettigrew
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  1. The George Washington University Medical Center, Washington, D.C., USA

    Gary Fiskum

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© 1996 Springer Science+Business Media New York

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Mattson, M.P. et al. (1996). βAPP Metabolites, Radicals, Calcium, and Neurodegeneration: Novel Neuroprotective Strategies. In: Fiskum, G. (eds) Neurodegenerative Diseases. GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0209-2_38

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  • DOI: https://doi.org/10.1007/978-1-4899-0209-2_38

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