DNA methylation changes as modulators of neuroinflammation in Alzheimer’s disease

Inflammation is an important mechanism underlying dementia and cognitive impairment in the elderly. It is implicated in the neuropathological cascade leading to amyloid plaques and it correlates with onset of Alzheimer’s disease (AD) and cognitive decline. Although DNA methylation might contribute to regulate many key inflammatory genes, the role of epigenetics on modulating inflammatory processes is yet poorly understood. Our current research seeks to identify changes in DNA methylation on inflammation-related genes associated with AD progression. Since clinical trials with anti-inflammatory drugs were unsuccessful at delaying AD progression, alternative strategies are urgently needed to tackle this crucial axis of disease. Manipulation of epigenetic modifications might represent a novel strategy and my studies may likely provide specific targets for intervention.

Funded by the Alzheimer’s Association, we completed genome-wide methylation analysis on postmortem frontal-cortex samples from subjects with AD and mild cognitive impairment (MCI) in comparison to control subjects (N=72) using microarray technology. We identified multiple differentially methylated regions (DMR) associated with immune response and inflammation genes in MCI and AD brains. Importantly, transcription of several of these genes, including chemokines and interleukins were deregulated in our in vitro system upon exposure of microglial cells to Amyloid Beta (A?) fragments. Furthermore, modulation of global methylation in vitro enabled us to identify decreased methylation as a step involved in the inflammatory cascade triggered by A?.