A Newly Discovered Version of Toxic Tau as a Therapeutic Target in Alzheimer's Disease

A newly identified form of tau presents targets for therapies, and the aim of this project is to evaluate two types of potential treatments.

Tau is a key protein in Alzheimer's disease, but that protein can take many different forms depending on its content. Daniel C. Lee, PhD, and his colleagues have discovered a new form of tau, one related to changes in the protein's building blocks. The changes involve swapping out the amino acid arginine for the amino acid citrulline at several spots on the protein. The resulting "citrullinated tau"" may be an especially toxic version of tau. The discovery presents citrullinated tau as a potential target for therapies in Alzheimer's disease. Dr. Lee and his colleagues plan to assess two therapeutic approaches that target tau citrullination. One approach will deploy antibodies that might inhibit the process of swapping the amino acids, so the tau never becomes citrullinated. The group has developed a toolkit of 11 antibodies that cover most of the sites where the amino acid swapping takes place on tau. The other candidate therapy is a vaccine against citrullinated tau. The team will test both potential therapies in lab models of Alzheimer's disease. Dr. Lee and his coworkers will compare the effects of the two approaches on disease progression and cognitive decline, opening up a new area of research in Alzheimer's disease.

This work represents a new area of tau pathobiology. The most innovative aspect of this application is the creation of our antibody toolkit of 11 highly specific citrullinated tau antibodies against the N-terminal domain, proline-rich region, microtubule binding region, and c-terminal domain region. Therefore, our research is positioned to test hypotheses and therapeutics that modulate 80% of tau’s citrullination sites.

Tau is unique in that soluble aggregates, insoluble aggregates, and tangles all associate with toxicity but manifest distinct clinical syndromes likely depending on the tau variant. This application will test the first immunotherapy and pharmacological inhibitor to citrullinated tau. As we define which citrullinated sites are the most influential on tau biology, we will employ new epitope targets for immunotherapy and inhibitors to reduce citrullination. We envision a new area of tau biology on citrullination for Alzheimer’s disease.