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Title: DNA methylation analysis of Alzheimer's disease
Author: Patel, Yogen
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2013
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There is evidence for a role for epigenetic mechanisms in Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder. The most studied epigenetic mark DNA methylation -the addition of a methyl group to cytosines located in CpG dinucleotides (5mC) - is known to change with aging and may reflect subtle changes in gene expression. Recently a second type of modified cytosine - a hydroxylated and methylated form (5hmC) - has been detected in the brain and maybe linked to the regulation of gene expression. Case-control differences in post-mortem brain DNA methylation were sought by examining both global DNA methylation and DNA methylation of two candidate genes relating to AD risk factors. Simultaneous assessment of 5mC and 5hmC methylation at a global level indicate hypomethylation of 5mC and hypermethylation of 5hmC in AD brain relative to controls, consistent with the notion that 5hmC serves as an intermediary form for demethylation of 5mC. Age was separately associated with a decrease in LINEl methylation and an increase in 5hmC methylation. The comorbidity of depression in AD was explored by assessing the methylation status of the serotonin transporter (SERT) gene promoter across several brain areas and showed tentative associations of disease with SERT CpG methylation. These measurable differences are very small and unlikely to represent any biological plausibility. In a subset of AD patients with additional clinical and behavioural measures there was no effect of SERT 5HTTLPR genotype on DNA methylation. The hypothesis that amyloid- deposition in brain is a consequence of amyloid precursor protein (APP) gene over-expression was examined by measuring DNA methylation across the APP gene region. AD status associates with methylation levels of several CpG sites within the 5' region CGI shore and exon 5 of the APP gene. However there are no co-occurring separate associations of total APP protein levels at these CpG sites. This study demonstrates the utility of the Fluidigm microfluidics platform to generate highly parallel bisulphite sequencing/baseĀ­ pair resolution CpG data.
Supervisor: Powell, John; Mill, Jonathan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available