A MOLECULAR MECHANISM FOR THE INDUCTION OF NEUROFILAMENT BUNDLING BY ALUMINUM IONS

Al induces neurofibrillary tangles in the perikaryon of neurons in vivo and in culture. The effect of Al ions complexed with maltol, a plant-derived ligand of Al, on purified neurofilament preparations was studied in vitro. The binding of Al to the arm-like projections of the high (H)- and medium (M)-molecular-weight neurofilament subunits causes a conformational change of the molecule (intrafilamentous reaction), characterized by an altered migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In addition, Al compounds strongly stimulate the interaction between neurofilaments (interfilamentous reaction). The possibility that phosphate groups of the H and M sidearms are involved in binding Al ions is discussed with regard to the migration on SDS-PAGE of dephosphorylated neurofilaments incubated with Al compounds and the alteration by Al ions of neurofilament phosphorylation in vitro by the associated kinase. Immunoblotting analysis of neurofilaments in cultivated neurons intoxicated with Al compounds revealed a similar Al-dependent alteration of the neurofilament subunit conformation. This result suggests that the mechanism of Al-induced bundling of neurofilaments derived from in vitro studies might be involved in the formation of tangles in situ.