Alzheimer’s disease (AD) is a neurodegenerative condition that is the most common cause of dementia in the UK. Key pathological hallmarks of AD include the extracellular accumulation of Amyloid-β (Aβ) plaques, the intracellular deposition of tau neurofibrillary tangles, and an increase in neuroinflammation which together contribute to cognitive decline. Genome wide association studies have identified numerous AD risk genes that are associated with microglial function. However, regulation of gene expression is not only influenced by the underlying DNA sequence but also by epigenetic regulation of temporal and spatial transcription. To date, our knowledge of how epigenetic regulation of microglia may contribute to AD onset and progression is limited. Previous studies have identified differentially methylated microglial genes in post-mortem human brains with advanced AD pathology1. However, epigenetic changes associated with the early stages of disease are yet to be fully explored.
In this study, we aimed to define the DNA methylation profile of human microglial genes associated with extracellular Aβ oligomer exposure and triage differentially methylated genes of interest.
Human iPSC derived differentiated microglia2,3 (KOLF 2.1J; N= 4 independent differentiations) were stimulated with either LPS/IFN-γ or oligomer enriched synthetic Aβ 1-42 for 24 hours and compared to an untreated control group. Microglia were then subjected to quantitative genome wide profiling for differential methylation using the Infinium Methylation EPIC BeadChip Platform (850k CpG sites). Differentially methylated sites between the experimental conditions were identified using a previously established analysis pipeline, and candidate genes triaged for further functional investigation. Ongoing work will assess the impact of mis-expressing these genes on AD relevant microglial functions.
Profiling of the human microglial methylation landscape in response to disease relevant extracellular challenges will expand our understanding of how epigenetic regulation drives transcriptional changes in AD, particularly in the early stages of disease. Better defined early epigenetic responses to Aβ may contribute to an improved understanding of disease onset and progression and offer novel targets for therapeutic intervention.