Exploring the Epigenome of Neurons and Glia in Vitro to Determine their Utility as a Model for Alzheimer's Disease

Abstract

Alzheimer’s disease is a progressive neurodegenerative condition that is characterised by distinct neuropathological changes. Within the last decade post mortem human brain samples have been used to show that there are robust epigenetic changes occurring in the brain during disease. However, as these samples are collected shortly after death they are a reflection of only the very end stages of disease. Through the exposure of differentiated adult cells to exogenous reprogramming factors it is now possible to generate induced pluripotent stem cells which have the potential to differentiate into any cell type in the body. Over recent years reseach has moved towards using these stem cells to generate neurons or microglia in order to study diseases of ageing such as Alzheimer’s disease. However, there are relatively few epigenetic studies that have been undertaken using induced pluripotent stem cells. As there are global cellular epigenetic changes occurring during the induction of pluripotency and re-differentiation it is critical to ensure we understand the DNA methylation changes occurring during normal neuronal differentiation before using these as a model of Alzheimer’s disease or other diseases of ageing. The aim of this thesis is to first characterise the DNA methylation changes that are occurring in neuronal and microglial models that are exposed to AD-relevant exposures such as differentiation and maturation, drug treatment and immune challenge. This will largely be achieved through measuring DNA methylation using the Illumina Infinium HumanMethylationEPIC BeadChip array which provides information on the DNA methylation levels at over 850,000 loci across the genome.