Development of Novel Models to Understand Tau Seeding in PSP and CBD

Pathway Grant

Principal Investigator: Dr. Abhirami Iyer, Washington University School of Medicine

Tauopathies, such as PSP and CBD, are characterized by the aggregation of the protein Tau. The location of Tau aggregates in the brain is highly correlated with disease symptoms and loss of affected tissue. Therefore, it has been proposed that Tau aggregation may be the key initial event in disease onset. However, how Tau aggregation initially begins in the context of disease is not known. In this proposal, we aim to identify the molecular mechanism(s) driving Tau aggregation in brain cells. We will use a novel model system that our lab has developed to screen for chemicals or cellular conditions that can promote the aggregation of Tau within cells. We will use relevant brain cell-types, advanced microscopy and RNA- sequencing techniques to characterize conditions that can trigger Tau aggregation. We propose to do this both in brain cell culture (Aim 1) as well as in a mouse model (Aim 2). Combining our results from Aims 1 & 2, we will be able to delineate the critical pathways necessary to promote Tau aggregation in PSP and CBD. Further, we will be able to describe new drug targets that could be pursued in the future for therapies.