UC San Diego

Alzheimer’s disease (AD) causes devastating decreases in cognitive ability and quality of life for more than 5 million Americans. Genetic AD risk factors have been well researched, but emerging evidence calls attention to epigenetic changes. In order to screen for changes in DNA methylation during AD, we analyzed genome-wide methylation data from postmortem human frontal cortex samples from AD (n=26), mildly cognitively impaired (n=24), and healthy subjects (n=22). We identified significant changes in methylation in genes related to inflammation, including CXCL17, IKBKAP, IKBKG, IL3, IL13, IL17RB, TNFRSF8, A2M, BDKRB1, and TNF in association with AD pathology.

The relationship of epigenetics and inflammatory pathways was further investigated with an in vitro model. It was hypothesized that the aberrant DNA methylation observed in AD brains causes dysregulation of inflammatory pathways in glial cells, contributing to the neuro-inflammation that is characteristic of AD. Global DNA methylation was modulated in vitro using S-adenosyl methionine to increase or Decitabine to decrease methylation in cultured human microglia, which resulted in activation of inflammation-related genes. Moreover, we identified similar transcriptional changes between cells treated with Decitabine and those activated by amyloid-β (Aβ), including deregulation of TNF, ICAM1, ITGB1, and TNFRSF1B. Importantly, Decitabine treatment of microglia also caused an increase in APP expression, further suggesting a link between changes in DNA methylation and elements of AD pathology.