Targeting tau hyperphosphorylation to develop novel therapeutics for Alzheimer’s Disease and other tauopathies

Alzheimer’s Disease (AD) is characterized by aggregates of Aβ and hyperphosphorylated tau. In 2025, AD affected an estimated 7.2 million Americans at a cost of $384 billion. Although immunotherapies targeting Aβ are approved, efficacy is limited, and there is reason to believe that tau provides a better target. However, no tau-targeting therapies are available. The approach here is based on our studies identifying a novel regulator of tau hyperphosphorylation. Moreover, this protein sits at the top of a hierarchy of events, providing the exciting prospect that the entire cascade of tau pathology can be blocked by targeting a single protein. A successful drug could revolutionize one of the major health challenges of our era. Our proposed approach is finding small molecules that modulate the activity of this regulatory protein. Proof-of-concept is provided by our finding that genetic and cell biological experiments targeting the protein can block neuron degeneration in cultured cells and in mice. Specific Aims are: (1) FRET-based screen for compounds altering the regulator’s interaction with other proteins, changing its activity; (2) DNA-encoded library screen for compounds binding the protein. Secondary assays include testing effects on downstream tau phosphorylation. Our overall goal is to set up assays and identify compounds leading to development of therapies for AD and other tauopathies.