Tau-mediated synaptic dysfunction in age-related neurodegenerative diseases

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Neurofibrillary tangles (NFTs) of the microtubule-associated protein tau are a universal feature of the aging brain. The extent of tau pathology throughout the brain correlates with both synapse loss and severity of cognitive impairment in age-related tauopathies. The ability to maintain cognitive function with a brain accumulating NFTs relies on the preservation and maintenance of synaptic networks. Therefore, understanding the mechanism by which tau contributes to network and synapse vulnerability is critical for developing preventative therapeutics. The goal of this proposal is to determine the cellular mechanism(s) by which pathologic tau drives neuronal network dysfunction. The experiments proposed in this application will uncover these mechanisms and provide intellectual and technical training for a successful transition into a postdoctoral position. The F99 phase (Aim 1) will test mechanistic cell biological hypotheses to better define how abnormal tau accumulation induces synaptic dysfunction, while providing opportunity to develop intricate experimental design and execution skills through cutting-edge biochemistry, microscopy, and electrophysiology techniques. The K00 phase (Aim 2) will build upon the F99 studies with computational strategies to integrate proteomics data from humans and experimental models to identify co-existing molecular changes that are highly relevant to age-related tauopathies.