The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid beta levels in Alzheimer's disease model mice

Alzheimer's disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., AppNL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, in this study, we treated AD model mice with CDDO-2P-Im. Overall design: To determine NRF2 inducers exerts therapeutic effects in Alzheimer's disease, a NRF2 inducer the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) was administered to Alzheimer's disease model AppNL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice at 30 micromol/kg body weight per os. We also 10%DMSO/10% Chremophol EL/PBS was used as a vehicle control. After treatment the mice 3 times per week, for 2 weeks to APP/TAU mice or for 4 weeks to AppNLGF mice. brain tissues were collected for sequencing analysis.