Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
J Biochem. 2024 Nov 4;176(5):405-414. doi: 10.1093/jb/mvae060.
Alzheimer's disease (AD) is the most common aetiology 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. App NL-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, we treated AD model mice with CDDO-2P-Im. We found that Aβ42 levels were markedly greater in the brains of AppNLGF mice than in those of APP/TAU mice. CDDO-2P-Im treatment significantly decreased Aβ42 levels, but not Aβ40 levels, in APP/TAU mice. Consequently, CDDO-2P-Im also decreased the ratio of Aβ42/Aβ40, a vital marker of amyloid plaque formation. LC-MS/MS analyses revealed that CDDO-2P-Im was delivered to the brains of the APP/TAU mice. CDDO-2P-Im induced the expression of detoxification and antioxidant gene targets of NRF2 and elevated reduced glutathione (GSH) levels in the mouse brain. These results support the notion that CDDO-2P-Im ameliorates AD-related pathologic changes.
阿尔茨海默病（AD）是痴呆症最常见的病因。转录因子 NF-E2 相关因子 2（NRF2）诱导编码 II 相解毒和抗氧化基因的基因表达。NRF2 受 Kelch 样 ECH 相关蛋白 1（KEAP1）调节，KEAP1-NRF2 系统是参与细胞保护的关键调节系统。为了研究 NRF2 表达的药理学诱导是否能减轻体内 AD 表型，我们使用了两种 AD 小鼠模型，即 App NL-G-F/NL-G-F（AppNLGF）和 APPV717I::TAUP301L（APP/TAU）小鼠。由于合成齐墩果酸三萜 1-[2-氰基-3,12-二氧代齐墩烷-1,9(11-二烯-28-酰基)]（CDDO）-4(-吡啶-2-基)-咪唑（CDDO-2P-Im）表现出很强的 NRF2 诱导活性，我们用 CDDO-2P-Im 处理 AD 模型小鼠。我们发现 AppNLGF 小鼠脑中的 Aβ42 水平明显高于 APP/TAU 小鼠。CDDO-2P-Im 治疗显著降低了 APP/TAU 小鼠中 Aβ42 的水平，但不降低 Aβ40 的水平。因此，CDDO-2P-Im 还降低了 Aβ42/Aβ40 的比值，这是淀粉样斑块形成的重要标志物。LC-MS/MS 分析显示，CDDO-2P-Im 被递送到 APP/TAU 小鼠的大脑中。CDDO-2P-Im 诱导了 NRF2 的解毒和抗氧化基因靶标表达，并提高了小鼠大脑中的还原型谷胱甘肽（GSH）水平。这些结果支持 CDDO-2P-Im 改善 AD 相关病理变化的观点。
