Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea.
AI-Based Neurodevelopmental Diseases Digital Therapeutics Group, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41062, Korea.
Mol Brain. 2024 Sep 2;17(1):62. doi: 10.1186/s13041-024-01137-y.
We previously demonstrated that felodipine, an L-type calcium channel blocker, inhibits LPS-mediated neuroinflammatory responses in BV2 microglial cells and wild-type mice. However, the effects of felodipine on tau pathology, a hallmark of Alzheimer's disease (AD), have not been explored yet. Therefore, in the present study, we determined whether felodipine affects neuroinflammation and tau hyperphosphorylation in 3-month-old P301S transgenic mice (PS19), an early phase AD mice model for tauopathy. Felodipine administration decreased tauopathy-mediated microglial activation and NLRP3 expression in PS19 mice but had no effect on tauopathy-associated astrogliosis. In addition, felodipine treatment significantly reduced tau hyperphosphorylation at S202/Thr205 and Thr212/Ser214 residues via inhibiting JNK/P38 signaling in PS19 mice. Collectively, our results suggest that felodipine significantly ameliorates tau hyper-phosphorylation and tauopathy-associated neuroinflammatory responses in AD mice model for tauopathy and could be a novel therapeutic agent for AD.
我们之前已经证明，L 型钙通道阻滞剂非洛地平可抑制 LPS 介导的 BV2 小胶质细胞和野生型小鼠的神经炎症反应。然而，非洛地平对阿尔茨海默病（AD）标志性病理 tau 蛋白的影响尚未得到探索。因此，在本研究中，我们确定了非洛地平是否会影响 3 月龄 P301S 转基因小鼠（PS19）中的神经炎症和 tau 过度磷酸化，PS19 是 tau 病的 AD 早期模型。非洛地平给药可降低 PS19 小鼠 tau 病介导的小胶质细胞激活和 NLRP3 表达，但对与 tau 病相关的星形胶质细胞增生无影响。此外，非洛地平通过抑制 PS19 小鼠中的 JNK/P38 信号通路，显著降低 tau 蛋白在 S202/Thr205 和 Thr212/Ser214 残基上的过度磷酸化。综上所述，我们的研究结果表明，非洛地平可显著改善 tau 过度磷酸化和 tau 病相关的神经炎症反应，是 tau 病 AD 模型的一种新型治疗药物。
