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Keywords:

  • drug discovery;
  • Alzheimer's disease;
  • zinc deficiency;
  • zinc enzymes;
  • zinc-aspartate;
  • therapeutic trials

Abstract

At the onset of Alzheimer's disease (AD), specific lesions occur in the hippocampus, i.e., neuropile-capillary amyloid (AM) plaques and neuronal paired-helical filaments (PHF)-neurofibrillary tangles (NFT). The hippocampus is the area of brain with the highest zinc content. Chemical investigations demonstrated that in AD, the cerebral zinc decreases, especially in the hippocampus. The mechanism may be the following: The primary, genetically determined, microvascular AM (asymptomatic) disturbs the blood-brain barrier, and metals (calcium, iron, aluminium, silicon, mercury, etc.( reach the cerebral cortex, where their levels increase and displace the zinc (whose level decreases) in some enzymes which become nonfunctional. The secondary production of PHF-NFT and the neuronal dysfunction responsible of the clinical symptoms of dementia may be related to the functional deficiency of the following zinc-enzymes: (1) those of DNA metabolism giving rise to abnormal DNA and therefore synthesis of abnormal proteins, constituting the NFT; (2) those involved in phosphorylating mechanisms at a post-transcriptional (ribosomal-mitochondrial) level, producing the abnormally phosphorylated tau protein, constituting the PHF; 3) that of glutamate (GLU) catabolism, resulting in a neurotoxic increase of GLU, producing PHF by abnormal phosphorylation of the neurofilaments; 4) those of neuronal detoxification contributing to the neuronal dysfunction. In regard to potential for therapeutic intervention, the timing needed for the AM-induced production of NFT, in the various areas of the brain, has been estimated to be about 14–67 months. During this time it may be possible to influence the AM-induced production of NFT: The chronic administration of neuroleptics enhances it, and the chronic administration of other drugs may reduce it. Such drugs may be zinc compounds, which will give an excess of zinc in the brain, will inhibit the above-mentioned AM induced by zinc deficiency, mechanisms producing the NFT related to the clinical symptoms of dementia, and therefore, may prevent, stop, delay, and even improve them. Preliminary trials with zinc-aspartate give promising results. Research is in progress to consolidate this zinc theory and to find more appropriate zinc compounds for this treatment. © 1992 Wiley-Liss, Inc.