German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Sci Rep. 2024 Aug 29;14(1):20123. doi: 10.1038/s41598-024-70837-1.
Modulation of the Nrf2 pathway, a master regulator of the antioxidant response and cellular metabolism, has been suggested as a promising therapeutic strategy in tauopathies, a heterogeneous group of neurodegenerative disorders characterized by intracellular proteinaceous inclusions of abnormally phosphorylated tau. Here, we explored the neuroprotective potential of different Nrf2-pathway activators in human immortalized dopaminergic neurons against annonacin-induced toxicity, a mitochondrial inhibitor associated with a PSP-like syndrome and capable of mimicking tauopathy-like features. Interestingly, we observed heterogenous and compound-dependent neuroprotective effects among the different Nrf2-pathway activators. With the exception of Fyn inhibitors, all the selected Nrf2-pathway activators improved cell viability and the oxidative status, and reduced the annonacin-induced tau hyperphosphorylation and neurite degeneration, particularly the p62-activators. However, improvement of the impaired mitochondrial function was only observed by the Bach-1 inhibitor. Surprisingly, we found evidence that ezetimibe, an approved drug for hypercholesterolemia, prevents the transcriptional upregulation of 4R-tau triggered by annonacin insult. Overall, our results suggest that the neuroprotective effects of the Nrf2-pathway activators against annonacin toxicity may rely on the specific mechanism of action, intrinsic to each compound, and possibly on the concomitant modulation of additional signaling pathways. Further research will be needed to fully understand how synergistic modulation of metabolic adaptation and cell survival can be exploit to develop new therapeutical strategies for tauopathies and eventually other neurodegenerative diseases.
调节 Nrf2 通路，作为抗氧化反应和细胞代谢的主要调节剂，已被认为是治疗神经tau 病的一种很有前途的治疗策略，神经tau 病是一组异质性神经退行性疾病，其特征是细胞内存在异常磷酸化 tau 的蛋白包涵体。在这里，我们研究了不同的 Nrf2 通路激活剂对 annonacin 诱导的毒性的神经保护潜力，annonacin 是一种与 PSP 样综合征相关的线粒体抑制剂，能够模拟 tau 病样特征。有趣的是，我们观察到不同的 Nrf2 通路激活剂之间存在异质的、化合物依赖性的神经保护作用。除了 Fyn 抑制剂外，所有选定的 Nrf2 通路激活剂都提高了细胞活力和氧化状态，减少了 annonacin 诱导的 tau 过度磷酸化和神经突退化，特别是 p62 激活剂。然而，只有 Bach-1 抑制剂改善了受损的线粒体功能。令人惊讶的是，我们发现证据表明，用于治疗高胆固醇血症的批准药物依折麦布可以防止 annonacin 损伤引发的 4R-tau 的转录上调。总之，我们的结果表明，Nrf2 通路激活剂对 annonacin 毒性的神经保护作用可能依赖于每个化合物特有的作用机制，以及可能对其他信号通路的同时调节。需要进一步的研究来充分了解代谢适应和细胞存活的协同调节如何被利用来开发针对 tau 病和最终其他神经退行性疾病的新治疗策略。
