Hyperphosphorylated tau and the molecular mechanisms of tauopathy Tauopathies are 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. Animal and cell studies demonstrated that soluble, oligomeric hyperphosphorylated tau is toxic to cells, and can transmit in a prion-like fashion in the brain. However, how hyperphosphorylation converts tau into a cytotoxic species, and how hyperphosphorylated tau exerts its cytotoxicity are unclear. As such, development of efficacious tauopathy therapeutics remains a formidable challenge. This R01 project aims to use a recombinant hyperphosphorylated tau (p-tau) as the model to examine the molecular mechanisms underlying tauopathies. Specifically, we wish to answer two major questions: how does hyperphosphorylated tau damage or kill cells? And what makes tau a cytotoxic species? We will perform proteomics studies to identify targets of p-tau that may lead to the realization of novel druggable targets for future therapeutics design. We will also pinpoint the phosphorylatable residues of the tau protein that, upon modification, drive the genesis and transmission of a pathogenic species. Finally, we have found that the formation of cytotoxic p-tau fibrils is subjected to the regulation of the ApoE lipoprotein and of selective metabolites of cholesterol. Biochemical and cell studies are to be performed to unravel the molecular details, which will facilitate our understanding of how different ApoE alleles contribute to the development of Alzheimer’s disease, as well as how cholesterol metabolism is mechanistically linked to this devastating disease.