Aluminum-induced neurofilamentous changes in cultured rat dorsal root ganglia explants

Intrathecal administration of aluminum (Al) salts to susceptible species causes prominent accumulations of neurofilaments (NFs) in neurons of the CNS. Involved nerve cells display abnormal phosphorylation of perikaryal NFs, impaired axonal transport of NFs, and reduced levels of mRNA for NF proteins. Further understanding of the pathogenesis of Al toxicity has been limited by difficulties inherent in the available in vivo systems. For this reason, we have developed a model to study the effects of Al on cultured sensory neurons. Explant cultures of rat dorsal root ganglia (DRG) were exposed to 1 mM aluminum lactate for 1 d, 3 d, or 7 d and then examined morphologically. Accumulations of NFs were noted as early as 1 d after exposure, and prominent masses of NFs were seen at 3 and 7 d. Northern analysis of mRNA extracted from the cultured ganglia showed that high, medium, and low molecular weight NF protein mRNA levels were markedly reduced compared to control values by 1 d of exposure. Class II β-tubulin mRNA was also moderately decreased. Reversibility of toxicity was assessed by removing the aluminum lactate from the medium after a 3 d exposure and examining the cultures 1 week later. The perikaryal masses of NFs dispersed and the levels of mRNA coding for the NF proteins and class II β-tubulin increased. The neurotoxic effects of Al on cultured DRG recapitulates the effects of intrathecal administration of Al on animals; this model produces similar changes in neuronal morphology with neurofilamentous masses and similar modifications of NF gene expression. The development of these NF abnormalities in neurons from rat DRG suggests that the apparent selective vulnerability of certain animal species and neurons to Al neurotoxicity is related to the access of the toxin to its target. This culture system will be useful for studying the effects of Al and possibly other toxins in a controlled setting.