Title: P3-178: ACTIVATION OF KEAP1-NRF2 SYSTEM MITIGATES OXIDATIVE STRESS AND NEUROINFLAMMATION IN THE ALZHEIMER'S DISEASE MODEL
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease and is a cause of 60% to 70% of cases of dementia. One of characteristics of neurodegenerative diseases are chronic but moderate levels of oxidative, inflammatory and metabolic stresses. The KEAP1-NRF2 system plays essential roles for cellular and organismal defense against oxidative and electrophilic stresses by regulating a battery of cytoprotective genes. In this study, we analyzed the effects of genetically and pharmacologically activated KEAP1-NRF2 system in the AD model mice. As an AD model, we utilized knock-in mice homozygous for humanized and mutated APP (AppNLGF) allele. The combinatorial mutants were generated by crossing AppNLGF mice with knock-down mice of an NRF2-inhibitor Keap1 (described as Keap1KD). Resultant combinatorial mutants (AppNLGF::Keap1KD) displayed reduced expression of oxidative stress marker such as 8-OHdG in the cerebral cortex compared to the AppNLGF mice. The behavioral tests suggested the reversed memory function in the AppNLGF::Keap1KD mutants. However, the expression of neuroinflammation markers such as Iba1 and Gfap were not significantly altered by qPCR analysis. Further detailed histological analysis revealed the differential distribution of IBA1-positive phagocytic cells around Amyloid b depositions among mutants. The decreased expression of inflammatory cytokine genes was also detected in the AppNLGF::Keap1KD mutants. We then treated AppNLGF with 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC), an activator of NRF2, in the drinking water for 11 months to analyze the effects of pharmacologically activated KEAP1-NRF2 system. 6-MSITC-treated AppNLGF mice also displayed reversed memory function and differential distribution of phagocytic cells compared to the vehicle-treated AppNLGF mice. These results suggest the activation of KEAP1-NRF2 system can mitigate AD-related phenotypes by regulating oxidative stress and inflammation.