A1 induces neurofibrillary tangles in the perikaryon of neurons in vivo and in culture. The effect of A1 ions complexed with maltol, a plant-derived ligand of A1, on purified neurofilament preparations was studied in vitro. The binding of A1 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, A1 compounds strongly stimulate the interaction between neurofilaments (interfilamentous reaction). The possibility that phosphate groups of the H and M sidearms are involved in binding A1 ions is discussed with regard to the migration on SDS-PAGE of dephosphorylated neurofilaments incubated with A1 compounds and the alteration by A1 ions of neurofilament phosphorylation in vitro by the associated kinase. Immunoblotting analysis of neurofilaments in cultivated neurons intoxicated with A1 compounds revealed a similar A1-dependent alteration of the neurofilament subunit conformation. This result suggest that the mechanism of A1-induced bundling of neurofilaments derived from in vitro studies might be involved in the formation of tangles in situ.