Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease
Abstract Background 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 Alzh...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02567-y |
| _version_ | 1798038819256139776 |
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| author | Yue Dong Hanqiao Yu Xueqi Li Kelong Bian Yayuan Zheng Mingrui Dai Xuejian Feng Yao Sun Yu He Bin Yu Haihong Zhang Jiaxin Wu Xianghui Yu Hui Wu Wei Kong |
| author_facet | Yue Dong Hanqiao Yu Xueqi Li Kelong Bian Yayuan Zheng Mingrui Dai Xuejian Feng Yao Sun Yu He Bin Yu Haihong Zhang Jiaxin Wu Xianghui Yu Hui Wu Wei Kong |
| author_sort | Yue Dong |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-04-11T21:45:34Z |
| format | Article |
| id | doaj.art-0ba0d8e95bab4125a2dc41d2c8de372e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T21:45:34Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-0ba0d8e95bab4125a2dc41d2c8de372e2022-12-22T04:01:25ZengBMCJournal of Neuroinflammation1742-20942022-08-0119111810.1186/s12974-022-02567-yHyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s diseaseYue Dong0Hanqiao Yu1Xueqi Li2Kelong Bian3Yayuan Zheng4Mingrui Dai5Xuejian Feng6Yao Sun7Yu He8Bin Yu9Haihong Zhang10Jiaxin Wu11Xianghui Yu12Hui Wu13Wei Kong14National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityAbstract Background 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12974-022-02567-yHyperphosphorylated tauNeuronal deathNecroptosisInflammationNF-κBAlzheimer’s disease |
| spellingShingle | Yue Dong Hanqiao Yu Xueqi Li Kelong Bian Yayuan Zheng Mingrui Dai Xuejian Feng Yao Sun Yu He Bin Yu Haihong Zhang Jiaxin Wu Xianghui Yu Hui Wu Wei Kong Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease Journal of Neuroinflammation Hyperphosphorylated tau Neuronal death Necroptosis Inflammation NF-κB Alzheimer’s disease |
| title | Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease |
| title_full | Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease |
| title_fullStr | Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease |
| title_full_unstemmed | Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease |
| title_short | Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease |
| title_sort | hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in alzheimer s disease |
| topic | Hyperphosphorylated tau Neuronal death Necroptosis Inflammation NF-κB Alzheimer’s disease |
| url | https://doi.org/10.1186/s12974-022-02567-y |
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