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(Continued from page 142)
the increase in glutamate.
Concentrations of glutamate can also be increased secondarily to a presynaptic stimulus of the glutamate release receptor. This increase could stimulate the calcium-dependent or independent channel. The impetus could once again be an abnormal protein, viral particle, or environmental toxin. The enhanced glutamate release would have the same result as a decreased glutamate uptake; namely, increased citric acid cycle intermediates and neurotoxicity.
The last possibility for presynaptic augmentation may be the glutamate metabotropic receptor. If this is stimulated, its second messenger, if aberrant, would continuously act at the presynaptic glutamate release receptor and augment glutamate with, again, the same results: increased citric acid cycle intermediates and neurotoxicity.
The lesions in AD occur in the glutamatergic pathways and not throughout the brain. A generalized system failure should demonstrate lesions throughout the brain. In blood, glutamate and aspartate are concentrated in red blood cells because of an active uptake mechanism that maintains low concentrations in the plasma. Plasma glutamate is mainly derived from intracellular loss.20 In the study by Ferrari and associates,2° which measures plasma compounds, the results are consistent with a decreased glutamate uptake. Other studies have demonstrated a 40% decrease in sodium-dependent glutamate uptake in AD.2-19
Initially normal glutamate levels may become neurotoxic as a consequence of reduced bioenergy,22,23 or hypoxia or ischemia,24 or the resultant oxygen free-radical production.25 Bioenergy is reduced by 70% to 100%, as demonstrated by the partial uncoupling of mitochondrial energy metabolism in in vitro studies reviewed by Greenamyre.22 In AD patients, thiamine-dependent mitochondrial enzymes were reduced significantly when compared with those in age-matched control subjects. The loss of these essential oxidative enzymes might result in cellular hypoxia and the release of neurotoxic levels of glutamate.22
Decreased bioenergy would stimulate the citric acid cycle with a subsequent increase in its intermediates a-ketoglutarate, and the products glutamate and aspartate. However, this stimulation should lead to widespread increases in all the citric acid cycle intermediates, which have not been documented. A decrease in glucose metabolism or adenosine triphosphate production would alter the resting membrane potential, and there would be a release of the voltage-dependent magnesium blockade of the N-methyl-D-aspartate (NMDA) channel. On the other hand, magnesium may be pathologically bound and not available to block the channel. In either instance, the normal synaptic concentration of glutamate would then become a potent and lethal toxin activating the receptor and allowing calcium influx.
Finally, with decreased energy, the glutamate metabotropic receptor would be stimulated with low-energy adenosine (AMP)-- (Continued on page 144)
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