A study on novel inhibitor of Tau aggregation and membrane binding of Tau aggregates

Abstract

Tau is an intracellular microtubule-associated protein that stabilizes microtubules. Under normal physiological conditions, Tau is a naturally unfolded and highly soluble protein. However, in Alzheimers disease, Tau is hyperphosphorylated and aggregated into intracellular neurofibrillary tangles (NFT). Aggregated Tau can transmit into adjacent cells and induce aggregation. This prion-like Tau propagation is an important mechanism for disease progression. Therefore, inhibition of aggregation and transmission of Tau can provide an important strategy for therapeutic agents of Alzheimers disease. In this study, we screened six novel inhibitors for Tau aggregation and designed one novel inhibitor based on the screened compounds structures. A total of 62 compounds were synthesized and 32 compounds efficiently inhibited Tau aggregation. Additionally, we developed a new measuring method for membrane binding of aggregated Tau. To measure aggregation-dependent membrane binding, fluorescence labeled Tau was utilized. Tau bound to living cell membranes by aggregation in a dose-dependent manner. In addition, using aggregation inhibitor, we confirmed that this method could be a convenient cell-based approach for validation or screening of membrane binding inhibitors.