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Calcium Homeostasis and Free Radical Metabolism as Convergence Points in the Pathophysiology of Dementia

  • Mark P. Mattson
  • Katsutoshi Furukawa
  • Annadora J. Bruce
  • Robert J. Mark
  • Emmanuelle Blanc
Part of the Contemporary Neuroscience book series (CNEURO)

Abstract

Realization that calcium and free radicals are key mediators of neuronal injury and death initially came from studies of acute neurodegenerative insults, such as ischemia or excitotoxic injury (see refs. 1 and 2 for review). At that time, many were skeptical (and some remain so) regarding the relevance of ischemic and excitotoxic injury to such disorders as Alzheimer’s disease (AD). Nevertheless, it is becoming increasingly appreciated that “final common pathways” of cell death are very similar in both acute and chronic neurodegenerative conditions. Central to such final common pathways are calcium and free radicals, which can be considered transducers of cell death in both acute and chronic neurodegenerative conditions. There also existed somewhat of a dichotomy among researchers focusing on mechanisms of “necrotic” and “apoptotic” cell death, wherein “apoptologists” believed that there existed fundamental mechanistic differences that distinguished apoptosis from necrosis. That is, apoptosis was considered a process of cellular suicide involving induction of the expression of “cell death genes,” whereas necrosis was a passive process resulting from an uncontrollable avalanche of ion influx and cell lysis (see ref. 3 for review). However, the more that mechanisms of cell death were studied, the more evident it became that calcium and free radicals are key mediators of both necrosis and apoptosis, and that the distinction between the two manifestations of cell death depended more on the quantity (severity and duration of the insult) than the quality of the insult. It is therefore critical that we understand the various genetic and environmental factors that influence neural calcium homeostasis and free radical metabolism. This translates into the following tacks of investigation:
  1. 1.

    Determining how mutations linked to specific neurodegenerative disorders impact on calcium regulation and free radical metabolism;

     
  2. 2.

    Identifying environmental factors that may compromise calcium homeostasis and promote free radical accumulation, and determining the specific molecular cascades involved; and

     
  3. 3.

    Elucidating the mechanisms whereby the brain normally resists neuronal degeneration (e.g., neurotrophic factor signal transduction pathways and acute response pathways).

     

Keywords

Nerve Growth Factor Hippocampal Neuron Amyloid Precursor Protein Calcium Homeostasis Domoic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Mark P. Mattson
  • Katsutoshi Furukawa
  • Annadora J. Bruce
  • Robert J. Mark
  • Emmanuelle Blanc

There are no affiliations available

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