| Alzheimer's disease (AD) is a progressive neurodegenerative disease. To investigate AD risk factors, we reviewed epidemiologic case control studies and recent research for AD's connection to the environment. Next, we examined the number one risk factor in AD, aging. We compared and contrasted lifespan profiles of AD-associated mRNA and protein levels in monkeys and mice. The AD-related biomarkers were APP mRNA and protein; Abeta levels; specificity protein 1 (SP1); and the beta-amyloid precursor cleaving enzyme (BACE1). In mice, APP and Sp1 mRNA and their protein products were elevated late in life; Abeta levels declined. In monkeys, APP, Sp1, and BACE1 mRNA declined in old age, while their protein products and Abeta levels rose. Proteolytic processing in both species did not match the production of Abeta. We further examined another specific risk factor that can alter AD related biomarkers: developmental lead (Pb) exposure. Our hypothesis was that Pb alters the lifespan profiles of AD-associated mRNA and protein levels in the rodent cortex but not in the cerebellum. APP mRNA and protein were initially elevated following developmental exposure, returned to basal levels in adulthood and remerged high late in life; Abeta1--42 levels were also increased. In the cerebellum there was no difference in the gene expression of APP between non-exposed and Pb-exposed animals. These data show that developmental Pb exposure has an effect on AD-related genes in regions associated with AD-pathology demonstrating that environmental conditions early in life can enhance neurodegeneration. Microarray analysis was conducted to take a genome wide view of what occurs with developmental Pb exposure. Gene expression of young and old animals was analyzed and genes that were down- and up-regulated (≥ 2 fold) were identified; 150 were significant. The major findings of this study found an up-regulation of genes related to the immune response, metal binding, metabolism and transcription/transduction coupling. In Pb-reprogrammed aging, there was a repression in these genes suggesting that disturbances in developmental stages of the brain had compromised the ability to defend against age-related stressors and thus may promote the neurodegenerative processes. |
