The brains of Alzheimer's disease (AD) patients are replete with senile plaques composed mainly of the beta-amyloid (Abeta) peptide. The proteolytic processing of the amyloid precursor protein (APP) provides the source and supply of Abeta; furthermore, elevated expression of the APP gene enhances Abetaproduction. The genetic regulation of genes is mediated by the transient short-term activity of transcription factors and the signals that influence them. DNA methylation of the promoter regions of genes is an epigenetic developmental event that sets the lifelong level of responsiveness of a gene. Previous developmental studies in our laboratory have revealed that environmental exposure to lead (Pb) interferes with the activity of the transcription factor Sp1, which is essential for APP gene expression. To examine latent responses to developmental insults by an environmental agent, we exposed rodents to Pb and monitored the lifetime expression of the APP gene. We found that APP mRNA expression was transiently induced in neonates, but exhibited a delayed over-expression 20 months after exposure to Pb had ceased. This late up-regulation in APP mRNA expression was accompanied by a rise in Sp1 activity. Furthermore, there was an elevation in APP and its amyloidogenic Abeta product at 20 months of age, in the developmentally Pb-exposed animals. In contrast, APP expression and Sp1 activity as well as APP and Abeta were unresponsive to Pb exposure during old age. These data suggested that environmental influences occurring during brain development pre-determined the expression and regulation of APP later in life. In addition to the APP promoter, other genes involved in APP processing pathway, such as beta-APP-cleaving enzyme (BACE) contain the Sp1 binding site in their promoters. Furthermore, over-expression of Sp1 potentiates BACE gene expression and APP processing to generate Abeta, while Sp1 knockouts reduced BACE expression. A potential mechanism by which Pb could promote neurodegeneration is by interfering with the epigenetic regulation of both APP and BACE genes established during early development. The regulatory region of both APP and BACE genes is rich in GC elements recognized by the transcription factor Sp1 and highly abundant in CG dinucleotides contained within and around the Sp1 DNA-binding site. Cytosine residues in the dinucleotide CG are the preferred substrates for DNA-methylation. The degree of DNA-methylation of CG sites in the promoters of genes results in gene silencing and sets the life-long level of responsiveness of promoters to the transcription factors that drive their expression. Therefore we hypothesize that exposure to Pb during early development results in the inhibition of the process of DNA-methylation of genes whose promoters are rich in GC box elements and CG dinucleotides. These early hypomethylating changes in the structure of the promoters would be maintained for the life of the organism and would render quiescent genes more responsive to stimuli, which appear during different stages of life. We would like to test this hypothesis by examining the effect of Pb exposure on DNA-methylation and determine whether these actions selectively impact genes rich in GC box elements such as APP and BACE.
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