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 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.

Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

“…In 2017, Caccamo et al first reported that the activation of the RIPK1/RIPK3/MLKL necrosome contributes to neuronal loss in both human AD brains and the AD mouse model . The connection of necroptosis and p-Tau has been confirmed that p-Tau is the key initiator of necroptosis in cultured neuronal cells and in an Tg­(Prnp-MAPT*P301s)­Ps19Vle/JNju AD mouse model . For the mechanism, RIPK1 was reported to be highly expressed by microglial cells in human AD brains and significantly higher in sporadic human AD brains than in health people but not RIPK3 .…”

“…The above results indicate that SZM679 treatment rescues the damaged hippocampal structure of AD mice. It has been evidenced that hyperphosphorylated Tau (p-Tau) is the key initiator of necroptosis in cultured neuronal cells . The AD biomarkers (p-Tau and Tau) were then tested.…”

“…The aggregated Tau hyperphosphorylation could result in microtubule destabilization, defective axonal transport, and neuronal damage. Recently, Dong et al found that p-Tau contributes to neuronal cell death primarily through the activation of necroptosis and the elevation of cytokine expression . In 2017, Caccamo et al first reported that the activation of the RIPK1/RIPK3/MLKL necrosome contributes to neuronal loss in both human AD brains and the AD mouse model .…”

“…Recently, Dong et al found that p-Tau contributes to neuronal cell death primarily through the activation of necroptosis and the elevation of cytokine expression. 34 In 2017, Caccamo et al first reported that the activation of the RIPK1/RIPK3/MLKL necrosome contributes to neuronal loss in both human AD brains and the AD mouse model. 15 The connection of necroptosis and p-Tau has been confirmed that p-Tau is the key initiator of necroptosis in cultured neuronal cells and in an Tg(Prnp-MAPT*P301s)Ps19Vle/JNju AD mouse model.…”

The role of regulatory necrosis in traumatic brain injury

“…( Liu et al, 2015 ; Sekerdag et al, 2018 ; Weiland et al, 2019 ; Hu et al, 2020 ; Dionísio et al, 2021 ). In Alzheimer’s disease, pTau can cause neuronal death by inducing necroptosis ( Dong et al, 2022 ), while introducing the gene of amyloid precursor protein (App) can enhance necroptosis ( Pang et al, 2022 ). In PD, fibrillar alpha-synuclein promotes the activation of neurotoxic astrocytes through RIP kinase signaling pathway ( Chou et al, 2021 ).…”