Age-dependent activation of microglia inflammatory state and its epigenetic modulation

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Project Summary This proposal addresses the epigenetic mechanisms of systemic microglia activation during ageing and its contribution to neurodegenerative diseases. Ageing in mice and human is associated with the increased expression of pro-inflammatory genes in microglia and microglia pro-inflammatory activation is considered one of the causes of age-associated neurodegenerative diseases including Alzheimer disease. The age-associated increase in microglia-driven inflammation is linked to an aberrantly heightened response of microglia to different inflammatory stimuli. The enhanced state of microglia activation during ageing resembles the state of trained immunity where initial immune cell exposure to various pro-inflammatory causes quantitate and qualitative long-lasting changes in cell responses to environmental triggers. We hypothesize that increased pro-inflammatory activity of microglia reflects the history of microglia exposure to inflammatory signals during animal or human life. We argue that infectious diseases, many of which can occur early in life, and the accompanied systemic inflammation exposes microglia to periphery-derived pro-inflammatory signals. Exposure to pro-inflammatory triggers can leave an epigenetic imprint that drives heightened inflammatory gene expression in ageing microglia. To test this hypothesis, we will induce transient systemic inflammation in mice followed by the analysis of gene expression at differed ages. The long-lasting changes in gene expression that follow innate immune cell activation has been previously linked to the activation of latent enhancers. We propose to determine the activation state of microglia enhancers after initial activation followed by the lifelong monitoring of the enhancer activity. We demonstrated that treatment of microglia with pharmacological inhibitors of BET proteins, that play a prominent role in enhancer activity, leads to the potent suppression of microglia activation in vitro and in vivo. Most notably, treatment with BET inhibitors has a major therapeutic impact on mice that suffer from AD. We will address the specific contribution of individual BET proteins to pro-inflammatory gene expression and enhancer activation during ageing and in neurodegeneration. This information is highly relevant for our understanding of the epigenetic mechanisms that govern the systemic age-associated microglial inflammatory state and may lead to the development of novel approaches for the treatment of neurodegenerative diseases.