Tauopathies are a group of neurodegenerative diseases that are characterized pathologically by neuronal loss and the accumulation of aggregates of the microtubule-associated protein Tau in surviving CNS neurons. Collectively, these disease, which include progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), are a common and important cause of progressive neurological disability in veterans. Current treatments only partially mitigate symptoms and do not alter the course of these diseases; consequently, there is an urgent need for new approaches that address pathogenic mechanisms and prevent disease progression. Convergent genetic and pathological evidence strongly suggests that Tau is centrally involved in causing neurodegeneration in these diseases, and there is accumulating evidence that microglial activation and pathological microglial synaptic pruning in response to Tau accumulation plays a key role in pathogenesis. However, there is limited understanding of the mechanisms regulating aberrant functions of microglia in tauopathy and whether this could be targeted by novel therapies. During the current funding period, we discovered that a chemical inhibitor of bromodomains (protein modules that bind acetylated lysine residues) rescues both neurological function and neuroinflammation in a novel zebrafish tauopathy model. By using CRISPR/Cas9 to make zebrafish genetic null mutants, we found that the chemical targets a bromodomain and extraterminal motif-containing (BET) protein, Brd4, which has previously been implicated in pro-inflammatory signaling. Building on this work, our overall guiding hypothesis is that: Brd4 is necessary for microglial activation and synapse elimination in tauopathy and is a valid therapeutic target for treatment of these diseases. To address this hypothesis directly in vivo, we have crossed our novel zebrafish tauopathy model with a transgenic line expressing a fluorescent reporter protein in its microglia, allowing direct intravital microscopic imaging of microglial dynamics in the intact brain in vivo (Aim 1A) and recovery of microglia by flow cytometry for gene expression analysis (Aim 1B). We will determine how microglial functions and transcriptional programs are altered in tauopathy and by modulation of Brd4. We will further restore Brd4 expression within microglia of Brd4-null zebrafish to establish whether critical functions of Brd4 in tauopathy are cell-autonomous to microglia (Aim 1C). We will next determine how Brd4 influences neuronal tauopathy, oxidative stress and synaptic integrity using intravital imaging and biochemical approaches (Aim 2). Finally, we will test all available bromodomain inhibitors, including some that have already been used in human clinical trials, for activity in preventing neurological and neuroinflammatory phenotypes in the zebrafish tauopathy model (Aim 3A). We will take the most promising candidate...