PROJECT ABSTRACT/SUMMARY: Tauopathies are a broad, prevalent, and lethal class of neurodegenerative disorders that affect up to 7 million Americans. There is a tremendous need for improved therapeutic strategies to treat the conditions that fall under this category, namely Alzheimer's disease (AD) and frontotemporal dementia (FTD). Recent work has begun to uncover critical roles for microglia, which are brain-resident macrophages, and the function of distinct microglial immune receptors in AD and FTD progression. Several immunoreceptor tyrosine-based activation and inhibitory motif-containing receptors, including TREM2, CD22, and CD33, have been identified in genome- wide association studies or animal studies. These receptors have been shown to have a critical impact on the progression of neurodegenerative diseases in AD. Interestingly, these receptors converge downstream at spleen tyrosine kinase (SYK). Recent findings from our lab have uncovered SYK's beneficial role in controlling disease outcomes in an amyloid beta (Aβ) amyloidosis mouse model of AD, where it was shown to be a central orchestrator of microglial activation. Given these insights, it is crucial to explore SYK's role in other types of degeneration, such as that caused by pathogenically phosphorylated tau (p-tau). In preliminary studies, I found that genetic ablation of microglia Syk in the tau-mediated PS19 mouse model of AD/FTD leads to a decreased p-tau burden, improved cognitive function, and maintenance of homeostatic microglia signature. Given these results, coupled with the general body of literature which concludes that aberrant innate immune activity is detrimental to tauopathy progression and drives increased tau hyperphosphorylation, I hypothesize that removal of SYK signaling, and subsequent dampening of microglial activation, will blunt tau-mediated neurological disease by promoting neuroprotective and anti-inflammatory functions in microglia. In Aim 1, I will investigate a microglial-specific role for SYK in modulating tauopathy and associated neurodegeneration. In Aim 2, I will study the mechanisms by which the loss of SYK specifically affects microglial activation to provide further understanding of the role of SYK signaling in neurodegeneration. Finally, in Aim 3, I will evaluate if genetically deleting microglial Syk offers an effective strategy to limit disease at a time point when PS19 mice exhibit signs of tau pathology and cognitive deficits. Completion of the proposed studies will break new ground in our understanding of the intracellular molecular mediators (i.e. SYK) that orchestrate immune responses in primary tauopathy and will further reveal how microglia activation contributes to neurodegenerative disease etiology. Moreover, this work is of potential translational significance as it will interrogate the therapeutic efficacy of SYK-inhibiting treatment in limiting the progression of AD and FTD.