National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, People's Republic of China.
Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130012, People's Republic of China.
J Neuroinflammation. 2022 Aug 15;19(1):205. doi: 10.1186/s12974-022-02567-y.
Progressive neuronal death is the key pathological feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying the neuronal death in AD patients have not been fully elucidated. Necroptosis reportedly activates and induces neuronal death in patients with Alzheimer's disease (AD); however, the main mediators and mechanisms underlying necroptosis induction in AD remain elusive.
The function of hyperphosphorylated tau (pTau) in inducing necroptosis in neuronal cell was examined using Western blotting, RT-PCR and flow cytometry. Tau-induced inflammation was identified via RNA sequencing and transwell assay. Pharmacological methods and CRISPR-Cas9 technology were used to verify the role of necrosome proteins in pTau-stimulated neuronal death and inflammation. TauP301S model mice were treated with Nec-1 s to evaluate the role of necroptosis in tau pathology.
Hyperphosphorylated tau could induce necroptosis in neuronal cells by promoting the formation of the RIPK1/RIPK3/MLKL necrosome. In addition, pTau significantly stimulated cell-autonomous overexpression of cytokines and chemokines via the intracellular nuclear factor kappa B (NF-κB) signaling pathway. Importantly, the RIPK1/RIPK3/MLKL axis was essential for the pTau-mediated NF-κB activation and cytokine storm. Furthermore, necroptosis stimulation, NF-κB activation, and cytokine induction have been detected in TauP301S mice and blocking necroptosis markedly ameliorated behavioral defects and excessive neuroinflammation in AD mice.
Our study, for the first time, revealed that pTau contributes to neuronal death by inducing necroptosis and inflammation, mediated by activating the RIPK1/RIPK3/MLKL and NF-κB pathways, thereby delineating the hierarchical molecular network of neuronal necroptosis induction in AD.
进行性神经元死亡是阿尔茨海默病（AD）的关键病理特征。然而，AD 患者神经元死亡的分子机制尚未完全阐明。据报道，细胞坏死诱导物（necrostatin）可激活并诱导阿尔茨海默病（AD）患者的神经元死亡；然而，AD 中诱导细胞坏死的主要介质和机制仍不清楚。
使用 Western blot、RT-PCR 和流式细胞术检测过度磷酸化的 tau（pTau）在诱导神经元细胞坏死中的作用。通过 RNA 测序和 Transwell 测定鉴定 tau 诱导的炎症。使用药理学方法和 CRISPR-Cas9 技术验证 necrosome 蛋白在 pTau 刺激的神经元死亡和炎症中的作用。用 Nec-1 处理 TauP301S 模型小鼠，以评估细胞坏死在 tau 病理学中的作用。
过度磷酸化的 tau 可通过促进 RIPK1/RIPK3/MLKL necrosome 的形成诱导神经元细胞坏死。此外，pTau 通过细胞内核因子 kappa B（NF-κB）信号通路显著刺激细胞自主过表达细胞因子和趋化因子。重要的是，RIPK1/RIPK3/MLKL 轴对于 pTau 介导的 NF-κB 激活和细胞因子风暴是必不可少的。此外，在 TauP301S 小鼠中检测到细胞坏死刺激、NF-κB 激活和细胞因子诱导，阻断细胞坏死可显著改善 AD 小鼠的行为缺陷和过度神经炎症。
本研究首次揭示，pTau 通过激活 RIPK1/RIPK3/MLKL 和 NF-κB 通路，诱导神经元坏死和炎症，从而导致神经元死亡，阐明了 AD 中神经元坏死诱导的层次分子网络。
