ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer's disease.
ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer's disease.
复制标题
内质网应激与阿尔茨海默病患者海马区TXNIP-NLRP3炎症体激活相关。
DOI：
10.1016/j.neuint.2021.105104
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发表时间：
2021-09
影响因子：
4.2
通讯作者：
Ishrat, Tauheed
中科院分区：
文献类型：
--
作者：
Ismael, Saifudeen;Wajidunnisa;Sakata, Kazuko;McDonald, Michael P.;Liao, Francesca-Fang;Ishrat, Tauheed
关键词：
虽然阿尔茨海默病（AD）的确切病因学尚不清楚，但实验和临床证据表明，神经炎症在AD的发病机制中起着重要作用。AD的病理特征是氧化还原状态失衡、内质网应激升高、突触功能障碍、炎症和进行性神经退行性变。已经注意到AD脑中淀粉样蛋白β（Aβ）和细胞内神经元缠结（NFT）的持续积累触发ER应激，这有助于神经变性。同样，实验证据支持这样的假设：硫氧还蛋白相互作用蛋白（TXNIP）是氧化还原调节剂硫氧还蛋白（TRX）的内源性调节剂，它被ER应激激活，并有助于激活AD大脑海马中的NLRP 3（NOD样受体蛋白3）炎症级联反应。在细胞和分子水平上分析死后人类AD和年龄匹配的非AD对照的海马的ER应激标志物和TXNIP-NLRP 3炎性体的表达。我们发现TXNIP在蛋白和转录水平上的高表达与AD的病理标志物如Aβ和NFTs密切相关。此外，我们的研究结果表明，TXNIP共定位于神经元和小胶质细胞。此外，AD海马中与ER应激相关的结合免疫球蛋白（BiP）、激活的真核起始因子2α（eIf 2 α）和C/EBP同源蛋白（CHOP）的表达均升高。此外，在AD海马中观察到NLRP 3炎性体活化的效应分子的表达升高，例如凋亡相关斑点样蛋白（ASC）、裂解的半胱天冬酶-1和裂解的白细胞介素-1 β。这项研究表明，TXNIP可能是连接ER应激与神经炎症的纽带。因此，TXNIP可能是一个可能的治疗靶点，以减轻AD发病机制中的神经炎症进展。
Although the exact etiology of Alzheimer’s disease (AD) is poorly understood, experimental and clinical evidences suggest the contribution of neuroinflammation in the pathogenesis of AD. Pathologically, AD brain is characterized by an imbalance in redox status, elevated endoplasmic reticulum (ER) stress, synaptic dysfunction, inflammation, and progressive neurodegeneration. It has been noted that continuous accumulation of amyloidbeta (Aβ) and intracellular neurofibrillary tangles (NFTs) in AD brain trigger ER stress, which contributes to neurodegeneration. Similarly, experimental evidences supports the hypothesis that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox regulator thioredoxin (TRX), is activated by ER stress and contributes to activation of NLRP3 (NOD-like receptor protein 3) inflammatory cascade in hippocampus of the AD brain. Hippocampus of postmortem human AD and aged matched non-AD controls were analyzed for the expression ER stress markers and TXNIP-NLRP3 inflammasome at cellular and molecular levels. We found higher expression of TXNIP at protein and transcript levels in close association with pathological markers of AD such as Aβ and NFTs in AD hippocampus. In addition, our results demonstrated that TXNIP was co-localized in neurons and microglia. Moreover, expression of binding immunoglobulin protein (BiP), activated eukaryotic initiation factor-2α (eIf2α) and C/EBP homology protein (CHOP), proteins involved the development of ER stress, were elevated in AD hippocampus. Further, elevated expression of effector molecules of NLRP3 inflammasome activation such as apoptosis associated speck-like protein (ASC), cleaved caspase-1 and cleaved interleukin-1β were observed in the AD hippocampus. The study suggests that TXNIP could be a link that connect ER stress with neuroinflammation. Thus, TXNIP can be a possible therapeutic target to mitigate the progression of neuroinflammation in the pathogenesis of AD.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1186/s13195-015-0126-1
发表时间：
2015
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Gomez-Nicola D;Boche D
通讯作者：
Boche D
HSF1 降解和 UPR 激活的双向相互作用促进 tau 过度磷酸化。
影响因子：
4.5
作者：
Kim E;Sakata K;Liao FF
通讯作者：
Liao FF
DOI：
10.3233/jad-2011-110890
发表时间：
2011
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Lloret A;Badia MC;Giraldo E;Ermak G;Alonso MD;Pallardó FV;Davies KJ;Viña J
通讯作者：
Viña J
影响因子：
7.8
作者：
Alberdi, Elena;Wyssenbach, Ane;Matute, Carlos
通讯作者：
Matute, Carlos