EXPERIMENTAL-MODEL OF MOTOR-NEURON DISEASE - ORAL ALUMINUM NEUROTOXICITY

To evaluate the pathogenetic role of environmental factors, especially metal intoxication, in amyotrophic lateral sclerosis (ALS), we conducted neuropathological and morphometrical studies of chronic oral aluminum (Al) neurotoxicity using young Japanese white rabbits fed a Ca- and Mg-deficient diet supplemented with Al-citrate for 7 to 19 months. Spheroids and globules, which were seen as axonal swellings packed with interwoven, small bundles of 10-nm neurofilaments, chromatolytic neurons, and degenerated neurons with satellite gliosis, were observed in the anterior horn of the spinal cord of rabbits treated with Al-citrate. Spheroids and globules were immunohistochemically stained with SMI 31, a monoclonal antibody for phosphorylated neurofilament heavy and medium epitopes. Compared to controls, the number of spheroids and globules was significantly increased in rabbits fed a Ca/Mg-deficient diet with and without chronic Al administration, and the number of large neurons (> 20 mu m in shortest diameter) in the fifth cervical spinal cord was decreased in rabbits fed a Ca/Mg-deficient diet with chronic Al administration. These changes in the present chronic Al intoxication model were more marked than those observed in our previous subacute study in which rabbits were intoxicated with Al for 1 month. Degenerated terminal buttons with accumulated neurofilaments were also observed in the spinal anterior horn of the chronic Al-treated rabbits. Chromatolytic change of motor neurons and axonal swellings (spheroids) in the spinal anterior horn are considered to be early changes in ALS, and the present findings in rabbits resemble these early changes. We speculate that Al, orally administered to rabbits, accumulates in the spinal cord and affects the processing or transport mechanisms of neurofilaments, the regulatory system of phosphorylation-dephosphorylation of cytoskeletal proteins, and the integrity of membrane function, or that it interacts with the phosphates of nucleic acids, leading to the development of neurofilamentous abnormality, chromatolytic and other degenerative changes in the anterior horn of the spinal cord. We consider oral Al intoxication, combined with a Ca/Mg deficiency, a reasonable experimental model to investigate the pathogenesis of ALS.