Using a novel mTBI model to investigate phosphorylation dependent common mechanisms in tauopathies

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Alzheimer’s disease (AD) and many related dementias (ADRDs) are tauopathies, characterized by somatodendritic accumulation of tau and intraneuronal inclusion bodies composed of tau species that have undergone extensive post translational modification. Although some disease-specific Tau modifications have been identified, many are conserved across the full range of tauopathies. We do not yet have a deep understanding of the molecular processes that generate these tau protein modifications, or of their functional consequences in promoting pathogenic cascades. This knowledge gap is a major contributor to our current inability to generate effective therapeutic interventions for AD and other tauopathies. The central hypothesis we are testing here is that a range of pathogenic events induce phosphorylation of tau at specific residues, resulting in mislocalization of tau within the cell and subsequent synaptic dysfunctions, and that inhibition of these early tau phosphorylation events will in turn inhibit tau pathologies and associated signaling deficits. This hypothesis is based on our published work, primarily utilizing cultured cell experimental systems. The direct relevance of this mechanism to human disease is further supported by the recent finding that phosphorylation of tau at these same specific residues is an early event preceding tau fibril formation in AD disease progression. Our overall objective here is to test and further refine this hypothesis in a novel mouse model we have developed (MAPT- GR) that expresses all isoforms of human tau at physiologic levels and ratios. We have found that mild traumatic brain injury (mTBI) induces a rapid phosphorylation and somatodendritic mislocalization of the human tau in these mice. Importantly, we can prevent this tau mislocalization by inhibiting phosphorylation. The specific aims are to: 1. Determine the dynamic changes in the subcellular distribution of phosphorylated tau. We will utilize our novel tauopathy model to test the working hypothesis that phosphorylation of tau at specific residues leads to somatodendritic accumulation of tau, tau mislocalization to dendritic spines, and alters micro- components of dendritic spines. 2. Determine the synaptic and circuit dysfunctions associated with the phosphorylation of tau. We will test the working hypothesis that mislocalization of phosphorylated tau to somatodendritic domains and dendritic spines results in synaptic and circuit dysfunction in our model. 3. Identify the impact of inhibiting these early phosphorylation events on tau mislocalization and associated signaling deficits. We will test our working hypothesis that mTBI activates GSK3β and CDK5, which phosphorylate the B and C domain of the tau protein. Expected Outcomes: We expect to identify the early-stage pathologies and dysfunctions caused by phosphorylation of tau and provide proof-of-concept demonstrations of the extent to which these dysfunctions can be prevented by blocking tau phosphorylation at specific residues. Of equal importance, we expect to have optimized a model and experimental platform in which potential therapeutic compounds that target this common disease mechanism can be tested and optimized.