ABSTRACT Alzheimer’s disease (AD) is a complex neurodegenerative disorder that progressively impairs cognitive abilities (e.g. memory) due to the loss of neurons in hippocampal and cortical regions of the brain. There are no available treatments that stop or slow the progression of AD, with the possible exception of the recently marketed monoclonal antibody drug Aducanumab. Previously approved AD therapeutics, which act by either inhibiting acetylcholinesterase or modulating the activity of N-methyl- D-aspartate receptors, are symptom-modifying only and just modestly effective. Investigating alternative therapeutic targets is an important step in the search for an effective AD therapy. The transcription factor Nurr1 (NR4A2) has been proposed as a novel therapeutic target for Alzheimer’s disease (AD), as the receptor regulates the expression of genes and cellular processes associated with the pathogenesis of AD. In particular, Nurr1 stimulates the expression of genes that reduce oxidative stress and inhibits the expression of genes that increase neuroinflammation. Although a few synthetic “Nurr1 agonists” have been reported in the scientific and patent literature, there is little evidence these ligands directly activate the receptor, with the exception of recent work on the antimalarial amodiaquine, steroidal anti-inflammatory drugs, and analogs of the endogenous Nurr1 ligand (DHI). Using an orthogonal drug development strategy, my lab has identified bona fide Nurr1 ligands that bind directly to the receptor’s ligand binding domain. Further, structural studies for three of these ligands reveal that each stabilizes Nurr1 in a different core conformation, and cellular assays demonstrate that each ligand regulates the expression of different genes. The proposed research seeks to capitalize on these findings to investigate the effect of Nurr1 ligands on the expression of genes and pathological processes associated with AD. We will determine Nurr1 ligand effects on the transcription of genes that modulate oxidative stress and responsiveness to inflammatory signals in cells treated with amyloid peptides and tau fibrils. In addition, we will determine Nurr1 ligand effects on the formation and secretion of Ab fibrils and the hyperphosphorylation and aggregation of tau protein. Successful completion of this project is expected to lay the foundation for rationally developing new AD therapeutics targeting Nurr1.