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Tesi etd-06012015-165546


Thesis type
Tesi di dottorato di ricerca
Author
TANNORELLA, PIERPAOLA
URN
etd-06012015-165546
Title
Folate metabolism, Alzheimer's Disease and Epigenetics
Settore scientifico disciplinare
MED/03
Corso di studi
SCIENZE BIOLOGICHE E MOLECOLARI
Commissione
tutor Prof. Migliore, Lucia
tutor Dott. Coppedè, Fabio
Parole chiave
  • Alzheimer's disease
  • mild cognitive impairment
  • folate metabolism
  • homocysteine
  • folate
  • epigenetics
  • DNA methylation
Data inizio appello
08/06/2015;
Consultabilità
parziale
Data di rilascio
08/06/2018
Riassunto analitico
The possible contribution of folate metabolism in modulating the methylation profile and the expression of disease-related genes has attracted substantial research in the field of complex diseases, such as Alzheimer’s disease (AD), likely resulting from still not well understood gene-environment interactions. Several hypotheses have been formulated linking impaired folate metabolism to AD risk, among them one of the most arguing suggests that it could result in altered DNA methylation and expression of genes involved in disease pathogenesis. <br>Aim of this project is to understand the correlation between folate metabolism and epigenetic modifications of genes related to AD. For this purpose, we screened 205 late onset Alzheimer’s disease (LOAD) patients, 74 subjects with Mild Cognitive Impairment (MCI) and 175 healthy controls for the presence of the common polymorphisms in folate metabolism gene, searching for association with disease risk. Moreover, we searched for correlation between each of the studied polymorphisms and available data on plasma homocysteine (Hcy), serum folate and vitamin B12 values. Finally, we analyzed analyzed the methylation levels of genes involved in amyloid-beta peptide production (PSEN1 and BACE1), in DNA methylation (DNMT1, DNMT3A and DNMT3B), and in one-carbon metabolism (MTHFR), searching for correlation with age and gender, with biomarkers of one-carbon metabolism. <br>We observed a significant increase frequency of MTRR 66G allele and MTRR 66GG genotype in AD patients with respect to controls and a significant increase frequency of MTR 2756G allele in MCI subjects. Several interactions between the studied polymorphisms and biochemical biomarkers were observed. <br>Methylation analysis revealed no difference in mean methylation levels between AD and control groups, but MCI patients showed higher methylation levels with respect the other groups in almost all the studied genes. MTHFR methylation showed an inverse correlation with age. Inverse correlation between plasma homocysteine and MTHFR, DNMT1 and PSEN1 methylation was observed. Positive correlation was observed between serum folate levels and MTHFR methylation. <br>
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