Abstract 2176 The Molecular Crosstalk between Cytochrome P450-Epoxide Hydrolase Metabolism of Polyunsaturated Fatty Acid and Neurodegeneration

This presentation explores the molecular interplay between the cytochrome P450-epoxide hydrolase (CYP-EH) metabolism of polyunsaturated fatty acid (PUFA) and neurodegeneration. While the PUFA CYP-EH metabolites are key lipid mediators for physiological processes, their role in neurodegeneration remains understudied due to the complexity of PUFA CYP-EH metabolism and the enigmatic nature of the mechanism of neurodegeneration. The central hypothesis of this project is that PUFA CYP-EH metabolism plays a critical role in neurodegeneration. To test this hypothesis efficiently, this project used Caenorhabditis elegans (C. elegans) as a simple model organism. C. elegans offers advantages such as easy handling and live imaging, high genetic homology to humans, genetic manipulability, adaptability to high throughput screening, and cost-effectiveness. This project employed an interdisciplinary approach by combining 1) novel C. elegans models that mimic amyloidosis, tauopathy and traumatic injury; 2) target metabolomics for determining PUFA CYP-EH metabolite profile in C. elegans models, and 3) a synthetic metabolic enzyme inhibitor for studying the role of PUFA CYP-EH metabolism on neurodegeneration. Our results reveal that 1) inhibition of PUFA CYP-EH rescues neurodegeneration induced by amyloid-β, tau, or mechanical injury and; 2) expression of amyloid-β and tau in neurons significantly affects PUFA CYP-EH metabolism. These results collectively demonstrate that PUFA CYP-EH metabolism plays a critical role in neurodegeneration. Furthermore, our study highlights C. elegans as a valuable complementary model for unraveling the complex mechanisms underlying the impact of PUFA CYP-EH metabolism on neurodegeneration. This study was supported by the National Institute of Aging R03 AG075465, the Pearl Aldrich Endowment for Aging Research, and startup funding from Michigan State University. J.H. is partially supported by NIEHS (T32 ES007255). The Pearl Aldrich Endowment for Aging Research Student award also partially supported M.S. and J.H.