Maternal hyperhomocysteinemia and epigenetic changes in fetal programming of genes involved in Alzheimer's Disease pathogenesis

Abstract

Epidemiological and experimental studies indicate that fetal and neonatal environment exerts a profound influence on physiological functions and may increase the risk of developing chronic diseases in adulthood. The hypothesis of fetal origins of adult disease, called fetal programming, suggests a correlation between an adverse intrauterine environment (nutritional deficiency or environmental stimuli) and adaptive responses in the fetus. It is believed that nutrition exerts its role in programming gene expression through the metabolism of groups of a carbon flow governed by the methionine-homocysteine. On this route, the methyl groups are available, among other purposes, for methylation of DNA and proteins and are sensitive to the supply of amino acids, folic acid, vitamin B12 and vitamin B6. In addition, recent studies have shown a change in the rate of global methylation in placenta of rats associated with placental levels of S-adenosyl-methionine (SAM), when compared to rats with diet homocysteine / folate deficient and homocysteine / folate supplementation. Another study observed a decrease in capacity of exploratory behavior and learning and memory associated with early deprivation of vitamin B. There are few studies about the effects of maternal hyperhomocysteinemia in the programming of fetal gene expression. Therefore, this study aims to investigate the effects of maternal hyperhomocysteinemia in different stages of fetal development and postnatal programming of genes APP, PS1, PS2, ADAM10, TACE, BACE and p53 that are important in the Alzheimer's disease pathogenesis. Swiss strain mices will be used, assigned to two experimental groups one month before pregnancy: control group, supplemented with methionine and deficient diet (methyl donors, vitamins B12, B2 and folate). After birth and at predetermined times, the kittens will be sacrificed and brain and plasma stored at -80ºC. The levels of homocysteine, SAM and S-adenosyl-homocysteine will be assayed by high performance liquid chromatography- HPLC, and serum folic acid and vitamin B12 will be performed by immunoassay technique. The quantification of gene expression will be performed by real-time PCR and quantification of protein expression by western blot. (AU)