The acidification of surface waters through acid precipitation has served to dramatically release aluminum ion from mineral stores. Along with the increasing concern over appearance of high aluminum ion concentrations in acidified waters has been the unequivocal demonstration of an association of aluminum with severla pathological states in man. Aluminum ion has been implicated in a variety of neurological, skeletal and cardiovascular disorders with an apparent environmental etiology. This proposal will focus on elucidation of the biochenical processes and molecular mechanisms through which alumunimun ion may express its potent and often selective neurotoxicity. We propose that aluminum will substitute for magnesium ion at critical enzume and regulatory sites with a concommitant depression of the rates for the magnesium ion-dependent processes. Importantly, it is the concentrationof free aluminum ion, not total aluminum ion burden or aluminum ion species, that is critical to expression of the pathological process. The selective neurotoxicity could therefore be a consequence of enhanced alunimun ion concentration (not accumulation) in neural tissue relative to serum or of an enhanced sensitivity of magnesium ion-dependent processes in neural tissue to aluminum ion-mediated inhibition. Our efforts will address both of these issues and focus on examination of agents and proteins in neural tissue, relative to serum, that may serve to enhance aluminum ion concentrations and minimize aluminum ion """"""""buffering"""""""" and on the inhibition by aluminum of magnesium ion- dependent enzymes in neural tissue involved in phosphate transfer.
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