Protein-like polymers (PLPs) are next generation biotherapeutics with the potential to improve treatment outcomes for patients suffering from devastating neurodegenerative diseases. We have developed a lead PLP that disrupts the Keap1-Nrf2 intracellular protein-protein interaction (PPI) that restricts the therapeutic activity of Nrf2 (nuclear factor-erythroid factor 2-related factor 2), a validated transcription factor target that regulates a system of hundreds of genes involved in protective responses against oxidative stress and proteostasis that has eluded selective intervention. This application is directly relevant to Alzheimer’s Disease/Alzheimer’s Disease Related Dementias (AD/ADRD) since enhanced Nrf2 activation in the brains of multiple mouse models of AD demonstrate significantly reduced AD associated pathology in the mice. The reduction in beta-amyloid levels, plaque numbers, and tau pathology in these models attest to the importance of Nrf2 in mitigating AD/ADRD. Thus, the studies outline in this proposal will lead to the development of completely novel Nrf2 activating biologics that could be used in the treatment of AD/ADRD. Preliminary data demonstrates that PLPs activate Nrf2 in primary cortical neurons in vitro and exhibit a 4d half-life in vivo. Our central objective is to optimize our PLP lead to improve its ability to activate Nrf2 in cells by tuning its architecture to balance its biochemical potency and cellular entry. Information from these studies will be used to nominate an advanced lead for follow-on Phase II pharmacodynamic studies in ARE-hPAP transgenic reporter and AD (APPK595N,M596L/PS1∆E9) models to nominate a development candidate, which will be the focus of our Phase II plan.