"Pathological deposition of hyperphosphorylated tau protein (p-tau) into neurofibrillary tangles in selective neurons is the most revealing molecular feature for a group of neurodegenerative disorders collectively known as tauopathies, including Alzheimer's disease (AD) which is the most common form of dementia. Tau pathology has a strong correlation with the progression and severity of cognitive functions, suggesting a pathogenic role of this protein, and critically, that measures that control tau deposition may afford promising therapy for tauopathies. The first hurdle for tangle-centric drug discovery would be the procurement of hyperphosphorylated tau (p-tau) exhibiting characters that are relevant to the disease. I have employed the PIMAX system (Protein Interaction Modules-Assisted function X) developed in our laboratory to produce recombinant p-tau. PIMAX p-tau is phosphorylated at multiple sites with strong links to the disease, and forms fibrils spontaneously. At sub-micromolar concentrations, p-tau triggers apoptosis, causes cytoplasmic superoxide levels to increase drastically, and causes death of two different cultured cells. Consistent with the neurodegeneration model that cytotoxic tau in the brain acts in a prion-like fashion, p-tau is able to potentiate the aggregation and cytotoxicity of the unphosphorylated tau that is otherwise benign to cultured cells. These unique features strongly suggest that p-tau is a novel and pathophysiologically relevant subject for AD drug discovery. I therefore developed a high-throughput screening platform for the identification of small-molecule compounds that may modulate the cognitive symptoms of AD through controlling the fibrillization and cytotoxicity of p-tau. In a pilot screen, I discovered two brain permeant prescription drugs, R-(--)-apomorphine and raloxifene to be cytoprotective p-tau aggregation inhibitors. In contrast, selective prescription benzodiazepines were found to exacerbate the cell killing activity of p-tau by enhancing its aggregation. Together, my results suggest that the p-tau aggregation-based screens may uncover candidates for AD therapy as well as potential avoidable risk factors for this devastating disease, therefore breaking through the current stagnant status of AD drug discovery."--Pages ii-iii.
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