Center for Alzheimer's and Related Dementias (CARD): Pharmacological Targeting of Tau Aggregates for Autophagic Removal in Alzheimer's Disease

National Institute On Aging

Investigators

Abstract

In the past year, we have identified a new class of compounds that bind to our protein of interest and tested these compounds in structural-activity relationship studies. We have begun to test compounds in cellular models and developed methods to screen chemical derivatives of these compounds. In the next year, we will identify a scaffold for our lead ligand to the protein of interest that avoids off-target effects. These efforts will further our understanding of this therapeutic strategy to target insoluble Tau protein aggregates for autophagic elimination. The milestones that we have achieved last year include as below. First, we successfully developed recombinant proteins against targeted domains of the FIP200 protein and confirmed their in vitro binding capabilities. Second, we determined small molecule binding sites in the FIP200 domain and completed structural characterization of target domains. Third, we performed DEL screen to identify FIP200 binding proteins and successfully identified primary FIP200 binding "hits" from screen. Last, we have developed tau protein aggregate cell models in an induced pluripotent stem cell model. Regarding the deliverables, we provided a series of small molecular weight ligands of the FIP200 protein and identified the lead compounds may lead to tau neurofilament degradation via autophagy. In the future, we aim to identify bioactive compounds that alter autophagy in living cells at low micromolar concentrations and create in vivo models of protein aggregation to test FIP ligands. Specifically, we expect to complete the to completed hits screen in late 2025 and start test the hits in iPSC-derived neurons with tau aggregate. We also expect to investigate compounds that enhance autophagy through VCP gene modulation. In summary, our project has achieved 100% completion on foundational deliverables, establishing a strong platform for subsequent development phases. The successful delivery of screening methodologies and lead compound identification represents critical milestones for therapeutic development.