NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression.
NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression.
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NLRP3 炎症小体依赖性高迁移率族盒 1 增加参与 Tau 过度表达引起的认知功能障碍
DOI：
10.3389/fnagi.2021.721474
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发表时间：
2021
影响因子：
4.8
通讯作者：
Zhou YG
中科院分区：
文献类型：
--
作者：
Zhao Y;Tan SW;Huang ZZ;Shan FB;Li P;Ning YL;Ye SY;Zhao ZA;Du H;Xiong RP;Yang N;Peng Y;Chen X;Zhou YG
Tau过度磷酸化是一种特征性的改变，存在于一系列神经系统疾病中，如创伤性脑损伤(TBI)和神经退行性疾病。针对高迁移率族蛋白1(HMGB1)的治疗在这些神经病理条件下产生神经保护作用。然而，对过度磷酸化的tau和HMGB1在神经炎症中的相互作用知之甚少。我们通过在小鼠体内注射编码人P301S tau基因的病毒，建立了受控皮质损伤(CCIS)模型和tau蛋白过度磷酸化模型，并通过免疫荧光、免疫印迹分析和行为学测试，阐明了磷酸化tau(p-tau)和HMGB1水平之间的相互作用。我们证明，在脑外伤和tau过度表达的小鼠，与空间记忆相关的脑区中p-tau和HMGB1水平升高。Tau过表达的动物也显著增加了核苷酸结合寡聚结构域样受体PYRP3的炎症体活性，表现为含有半胱氨酸酶招募结构域的凋亡相关SPECK样蛋白增加，激活Caspase-1和IL-1β(IL-1β)水平。此外，NLRP3-/-小鼠和HMGB1抑制剂甘草甜素被用来探索p-tau过表达疾病的治疗策略。与野生型(WT)tau过表达小鼠相比，NLRP3-/-小鼠中p-tau和HMGB1的表达下调，表明HMGB1的改变是NLRP3依赖的。此外，晚期应用甘草酸苷显著降低了p-tau水平，改善了在Y迷宫和T迷宫中的表现，并提高了tau过度表达的小鼠筑巢的能力，这表明空间记忆和高级海马体功能得到了改善。研究结果表明，p-tau以NLRP3依赖的方式在神经炎症和空间记忆的调节中具有触发作用，并提示HMGB1抑制剂治疗tauopy可能是一种更好的治疗策略。
Tau hyperphosphorylation is a characteristic alteration present in a range of neurological conditions, such as traumatic brain injury (TBI) and neurodegenerative diseases. Treatments targeting high-mobility group box protein 1 (HMGB1) induce neuroprotective effects in these neuropathologic conditions. However, little is known about the interactions between hyperphosphorylated tau and HMGB1 in neuroinflammation. We established a model of TBI with controlled cortical impacts (CCIs) and a tau hyperphosphorylation model by injecting the virus encoding human P301S tau in mice, and immunofluorescence, western blotting analysis, and behavioral tests were performed to clarify the interaction between phosphorylated tau (p-tau) and HMGB1 levels. We demonstrated that p-tau and HMGB1 were elevated in the spatial memory-related brain regions in mice with TBI and tau-overexpression. Animals with tau-overexpression also had significantly increased nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation, which manifested as increases in apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), activating caspase-1 and interleukin 1 beta (IL-1β) levels. In addition, NLRP3–/– mice and the HMGB1 inhibitor, glycyrrhizin, were used to explore therapeutic strategies for diseases with p-tau overexpression. Compared with wild-type (WT) mice with tau-overexpression, downregulation of p-tau and HMGB1 was observed in NLRP3–/– mice, indicating that HMGB1 alterations were NLRP3-dependent. Moreover, treatment with glycyrrhizin at a late stage markedly reduced p-tau levels and improved performance in the Y- and T-mazes and the ability of tau-overexpressing mice to build nests, which revealed improvements in spatial memory and advanced hippocampal function. The findings identified that p-tau has a triggering role in the modulation of neuroinflammation and spatial memory in an NLRP3-dependent manner, and suggest that treatment with HMGB1 inhibitors may be a better therapeutic strategy for tauopathies.
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DOI：
10.1016/j.bbi.2017.11.018
发表时间：
2018-08
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Kigerl KA;Lai W;Wallace LM;Yang H;Popovich PG
通讯作者：
Popovich PG
影响因子：
16.2
作者：
Kaufman SK;Sanders DW;Thomas TL;Ruchinskas AJ;Vaquer-Alicea J;Sharma AM;Miller TM;Diamond MI
通讯作者：
Diamond MI
影响因子：
5.7
作者：
Chavan, Sangeeta S.;Huerta, Patricio T.;Diamond, Betty
通讯作者：
Diamond, Betty
胰高血糖素样肽-1 保护海马神经元免受晚期糖基化终产物诱导的 tau 蛋白过度磷酸化
影响因子：
3.3
作者：
Chen, S.;An, F. -M.;Gao, X. -D.
通讯作者：
Gao, X. -D.
NLRP3/ASC介导的肺泡巨噬细胞焦亡增强体外循环所致急性肺损伤中HMGB1的分泌
影响因子：
5
作者：
Hou, Lei;Yang, Zhongwei;Wang, Xiangrui
通讯作者：
Wang, Xiangrui