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Glutamate, beta-amyloid precursor proteins, and calcium mediated neurofibrillary degeneration

  • V. L. Smith-Swintosky
  • M. P. Mattson
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 44)

Summary

In this article we present evidence supporting the interaction between excitotoxicity, βAPP mismetabolism, metabolic compromise and intracellular calcium destabilization in the process of neurodegeneration associated with Alzheimer’s disease (AD). AD is characterized by the presence of neurofibrillary tangles and amyloid-containing plaques in specific regions of the brain. There appear to be several processes which contribute to the neurodegeneration associated with AD. Although AD has been linked to genetic mutations on chromosomes 21, 19 and 14, there are sporadic forms of AD that have no known genetic mutation involved. Aging is the major risk factor for AD. During the course of normal aging several metabolic compromises may occur in the brain. Both decreased glucose transport and utilization, and increased glucocorticoid levels are known to occur with aging and may lead to decreased energy supplies, ATP depletion, failure of Ca2+ buffering systems, excess glutamate release and activation of glutamate receptors. In addition, a reduction in antioxidant enzymes and consequently an increase in free radicals has also been associated with aging. Each of the preceeding alterations would lead to an increase in neuronal [Ca2+]i. Elevated calcium could then activate calcium-dependent proteases which degrade particular cytoskeletal proteins, and lipases which generate free radicals resulting in membrane damage and possible cell death. In this article we provide evidence that amyloid β-peptide (Aβ), the substance which accumulates in AD plaques, exacerbates excitotoxic and metabolic compromises to neurons resulting in changes in the cytoskeleton which resemble those seen in the neurofibrillary tangles of AD. We also provide evidence that secreted forms of β-amyloid precursor protein (βAPP) are neuroprotective against excitotoxic insults. Recent findings concerning the normal function of βAPP and the mechanism of Aβ toxicity place βAPP at the center of changes leading to neuronal degeneration in AD.

Keywords

Nerve Growth Factor Hippocampal Neuron Amyloid Precursor Protein Excitatory Amino Acid Receptor Neurofibrillary Degeneration 
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-Verlag 1994

Authors and Affiliations

  • V. L. Smith-Swintosky
    • 2
  • M. P. Mattson
    • 1
    • 2
  1. 1.Sanders-Brown Research Center on AgingUniversity of KentuckyLexingtonUSA
  2. 2.Department of Anatomy and NeurobiologyUniversity of KentuckyLexingtonUSA

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