Unique Al Organic Complexes Comparative Neurotoxicity

             The potential role of aluminum in the etiology and pathogenesis of Alzheimer’s disease is unclear. Although aluminum accumulates in the abnormal nerve cells seen in the brains of the victims of Alzheimer’s disease, the biologic antecedents and consequences of this observation remain poorly understood. One of the major obstacles to progress in understanding aluminum’s effects on the nervous system has been the almost exclusive use of inorganic salts of aluminum for experimental studies. Such inorganic aluminum salts are relatively insoluble in body fluids and therefore these reagents represent poor ingredients for experiments on the toxic effects of aluminum on the brain.               In this application we propose to establish a chemistry laboratory in which we will synthesize a number of unique aluminum containing compounds in which the metal is linked to organic molecules. These organic-aluminum complexes will possess greatly increased solubility characteristics, speeding their entry and distribution in the brain, and enhancing their neurotoxic capacities. We will also synthesize aluminum-containing compounds linked to important constituents for nerve cell functioning. We predict that these latter two compounds will selectively enter nerve cells through the use of specialized chemical pathways responsible for recycling these normal constituents into the cell.         Each of the 5 newly synthesized compounds will be purified, and characterized chemically. Following this, varying doses of each compound will be introduced into the brains of rabbits. Rabbits are used because they are particularly sensitive to the toxic effects of aluminum and form changes in the nerve cells that are similar to those seen in patients with Alzheimer’s disease . The animals will be observed for signs of neurologic impairment and will subsequently be humanely sacrificed and examined for morphologic evidence of toxic effects. Control animals will receive inoculation of each of the same compounds except these will lack aluminum. In this way, the comparative toxicity of each of these unique organic aluminum compounds will be determined .