Inhibition of the CEBPβ-NFκB interaction by nanocarrier-packaged Carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimer's disease model.
Inhibition of the CEBPβ-NFκB interaction by nanocarrier-packaged Carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimer's disease model.
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DOI：
10.1038/s41419-022-04765-1
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发表时间：
2022-04-07
影响因子：
9
通讯作者：
Chun-Yan W
中科院分区：
文献类型：
--
作者：
Yi-Bin W;Xiang L;Bing Y;Qi Z;Fei-Tong J;Minghong W;Xiangxiang Z;Le K;Yan L;Ping S;Yufei G;Ye X;Chun-Yan W
神经炎症发生在阿尔茨海默病（AD）的早期。AD的初始阶段与胶质细胞功能障碍有关，其导致Aβ清除障碍和突触连接破坏。CEBPβ是CCAAT增强子结合蛋白（CEBP）家族的成员，调节炎症相关基因的表达，并且其表达在经历变性和损伤的脑中升高。然而，AD中CEBPβ介导的慢性炎症的潜在机制尚不清楚。在这项研究中，我们观察到细胞核CEBPβ水平的增加促进了CEBPβ与NFκB p65亚基的相互作用，增加了APP/PS 1小鼠脑中促炎细胞因子的转录。经口给予纳米载体包装的鼠尾草酸（CA）可减少APP/PS1小鼠脑中小胶质细胞和星形胶质细胞的异常活化，并减少成熟IL-1β、TNFα和IL-6的产生。CA给药可减少APP/PS1小鼠的β-淀粉样蛋白（Aβ）沉积，并改善认知障碍。我们观察到CA阻断了CEBPβ与NFκB p65的相互作用，染色质免疫沉淀显示CA降低了NFκB靶基因TNFα和IL-6的转录。我们证实CA通过抑制CEBPβ-NFκB信号通路减轻炎症介质诱导的神经元变性并减少Aβ分泌。采用磺丁基醚-β-环糊精（SBEβCD）作为CA纳米载体的包封剂，克服了CA水溶性差的缺点，提高了CA的脑生物利用度。CA纳米粒无明显毒性。我们展示了一种可行的基于SBEβ CD的靶向脑的纳米递送系统。我们的数据提供了实验证据表明，CA负载的纳米颗粒是潜在的治疗剂，用于AD治疗。
Neuroinflammation occurs early in Alzheimer’s disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aβ clearance and disruption of synaptic connection. CEBPβ, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBPβ-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPβ facilitated the interaction of CEBPβ with the NFκB p65 subunit, increasing the transcription of proinflammatory cytokines in the APP/PS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1β, TNFα and IL-6 production in the APP/PS1 mouse brain. CA administration reduced β-amyloid (Aβ) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBPβ with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aβ secretion by inhibiting the CEBPβ-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEβCD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBEβCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.
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影响因子：
4.3
作者：
Frozza RL;Lourenco MV;De Felice FG
通讯作者：
De Felice FG
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
8
作者：
Fröhlich E
通讯作者：
Fröhlich E
影响因子：
3.7
作者：
de Jong, Danielle;Jansen, Rene;Kremer, Berry
通讯作者：
Kremer, Berry
影响因子：
9.3
作者：
Krstic D;Madhusudan A;Doehner J;Vogel P;Notter T;Imhof C;Manalastas A;Hilfiker M;Pfister S;Schwerdel C;Riether C;Meyer U;Knuesel I
通讯作者：
Knuesel I