Research Project
10265535
PROJECT SUMMARY Tauopathies are a group of neurodegenerative disorders sharing the common pathology of the tau protein in the central nervous system. The most prominent tauopathy is Alzheimer?s disease (AD) that affects nearly 6 million Americans and more than 30 million people worldwide. Additional tauopathies include frontotemporal lobar degeneration with tau, Pick?s disease, progressive supranuclear palsy, and chronic traumatic encephalopathy. Tauopathy patients suffer from progressive decline of cognitive and other neurological functions. Clinical manifestations correlate with the spatiotemporal distribution of neuronal and glial inclusions of abnormally phosphorylated tau (p-tau). Animal and cell studies demonstrated that soluble, oligomeric p-tau are toxic to cells, and can transmit between cells by nucleating the pathological tau aggregation in a prion-like fashion. Accordingly, molecules that inhibit or enhance the aggregation and cytotoxicity of p-tau are potential therapeutics and risk factors, respectively. However, tau-centric drug discovery has not come to fruition due primarily to the lack of a reliable and simple system for the synthesis of pathologically relevant p-tau. During the course of a Phase I STTR grant (1R41AG057274), we used the PIMAX system to synthesize four isoforms of p-tau bearing a core phosphorylation pattern highly relevant to the disease. We developed kinetics assays for p-tau aggregation, and cell-based assays for the cytotoxicity of p-tau. Importantly, we conducted a chemical library screen that identified both p-tau aggregation inhibitors and enhancers that had been linked previously to dementia and Alzheimer's disease. These achievements met and exceeded the milestones outlined in the original Phase I project. The goal of the current Phase II SBIR project is to develop assay kits to support the identification of therapeutics and risk factor of tauopathies, including Alzheimer's disease. In addition, using the cytotoxic p-tau synthesized in our facilities, we will raise antibodies recognizing the pathogenic epitope of p-tau. If successful, this will lead to the development of early diagnostic reagents and even novel tauopathy antibody therapies. By integrating complementary and synergic expertise of teams from industry and academia, this SBIR project will have solid impact on drug development, prevention, and diagnosis of Alzheimer?s disease and other tauopathies.
