Recently, inhibitors of histone deacetylase enzymes (HDACs) have been identified as having potential therapeutic value for a range of neuronal disorders including Alzheimer’s disease, dementia and stroke [1, 2]. The HDAC inhibitors have been shown to have neuroprotective and anti-inflammatory properties yet their mechanism of action remains unidentified. We have recently shown that microglia activation by a number of insults (eg Amyloid beta, LPS and interferon) can be reduced by HDAC inhibitors . Using siRNA we have identified HDAC1 and HDAC2 as the important HDAC enzymes for this response . Whilst still don’t know the mechanism by which HDAC inhibitors block microglia activation we have shown that it doesn’t require new protein synthesis so is unlikely to be a result of the well characterised effect of these inhibitors on increasing gene expression. We are currently investigating the cellular mechanism(s) involved in the inhibition and identifying the molecular targets involved. Current HDAC inhibitors are non-selective and their long-term use is thought to impair cognition due to widespread off target effects and identifying the mechanism by which they reduce excessive microglia activation would open up novel therapeutic targets for the treatment of neurodegenerative disorders.
We have a number of candidate proteins that are known to be involved in regulating microglia activation and are modulated by acetylation. We plan to test these candidates and we are currently performing a screen of all microglia proteins to identify which proteins are differentially acetylated in response to microglia activation and HDAC inhibition which should provide novel targets to characterise. The project will involve the use of cell culture methods of primary and immortalised microglia, functional assays to quantify cell responses such as proliferation, apoptosis and migration as well as biochemical and molecular approaches to quantify cytokine production (ELISA) and changes in gene and protein expression (RT-PCR, western, immunofluorescence).
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