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

Akira Uruno, Shiori Kadoguchi-Igarashi, Ritsumi Saito, Shohei Koiso, Daisuke Saigusa, Ching-Tung Chu, Takafumi Suzuki, Takashi Saito, Takaomi C Saido, Antonio Cuadrado, Masayuki Yamamoto
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Abstract

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., 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.
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NRF2 诱导剂 CDDO-2P-Im 可降低阿尔茨海默病模型小鼠的淀粉样蛋白 β 水平
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)诱导编码第二阶段解毒和抗氧化基因的表达。NRF2 受 Kelch-like ECH-associated protein 1(KEAP1)调控,而 KEAP1-NRF2 系统是参与细胞保护的关键调控系统。为了研究药理诱导 NRF2 的表达是否能缓解体内的 AD 表型,我们采用了两种 AD 小鼠模型,即 App NL-G-F/NL-G-F (AppNLGF)和 APPV717I::TAUP301L (APP/TAU)小鼠。由于合成的齐墩果烷三萜类化合物 1-[2-氰基-3,12-二氧代油橄榄-1,9(11-二烯-28-酰基)](CDDO)-4(-吡啶-2-基)-咪唑(CDDO-2P-Im)具有很强的 NRF2 诱导活性,因此我们用 CDDO-2P-Im 处理 AD 模型小鼠。我们发现,AppNLGF小鼠大脑中的Aβ42水平明显高于APP/TAU小鼠。CDDO-2P-Im 能显著降低 APP/TAU 小鼠脑中 Aβ42 的水平,但不能降低 Aβ40 的水平。因此,CDDO-2P-Im 还降低了 Aβ42/Aβ40 的比率,而 Aβ42/Aβ40 是淀粉样斑块形成的重要标志。LC-MS/MS分析显示,CDDO-2P-Im被输送到了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点的表达,并提高了小鼠大脑中还原型谷胱甘肽(GSH)的水平。这些结果支持了 CDDO-2P-Im 可改善注意力缺失症相关病理变化的观点。
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