ALUMINUM, NEUROTOXICITY AND GENE EXPRESSION

铝被认为是阿尔茨海默氏症的一种可能的病因

Aluminum has been implicated as a possible etiological agent in Alzheimer's disease in view of the fact that high concentrations of aluminum are found in neurons affected with the Alzheimer's neurofibrillary tangles. Furthermore, the injection of aluminum into the rabbit cerebral spinal fluid induces accumulation of neurofilaments in the perikaryon and cell processes. We have performed preliminary experiments and have shown that aluminum chloride degrades naked DNA in vitro. Experiments are proposed to determine whether transcribing genes are more sensitive than non-transcribing genes to damage by aluminum. Since aluminum ions enter cultured cells, we will examine the effect of aluminum on different levels of gene expression in vivo using the ras oncogene which is expressed in the human neuroblastoma cell line SK-N-SH. These results will be compared to those results obtained using the beta-interferon gene which is a nontranscribing gene in the cell line. In addition, the effect of aluminum on different regions of SV40 minichromosome will be ascertained. A 400 bp region spanning the replication origin is devoid of histones. We will examine whether this 400 bp region is more susceptible to aluminum than other portions of the minichromosome. The effect of aluminum on ras mRNA and on the synthesis of the ras protein in SK-N-SH cells will also be determined. Finally, the effect of aluminum on the expression of the plasmid-coded G418 antibiotic resistance gene which will be introduced into SK-N-SH cells by DNA transfection technique will be determined. These results should indicate whether genes show a differential sensitivity to damage by aluminum, and whether histones might be involved in the protection of DNA from aluminum. In either case, a foundation would be established for further studies of aluminum toxicity in degenerative disease.