Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition.
Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition.
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通过NFAT抑制作用的小鼠模型中小胶质细胞激活的衰减。
DOI：
10.1186/s12974-015-0255-2
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发表时间：
2015-03-04
影响因子：
9.3
通讯作者：
Combs CK
中科院分区：
文献类型：
--
作者：
Rojanathammanee L;Floden AM;Manocha GD;Combs CK
淀粉样蛋白β (Aβ)肽被假设刺激小胶质细胞获得阿尔茨海默病（AD）大脑的特征性促炎表型。Aβ导致小胶质细胞活化的具体机制仍然是确定有吸引力的干预分子靶点的一个感兴趣的领域。基于小胶质细胞表达促炎转录因子、活化T细胞核因子（NFAT）这一事实，我们假设疾病期间发生的a β刺激的小胶质细胞增生需要NFAT活性。在缺乏或存在NFAT抑制剂、FK506和tat-VIVIT肽的情况下，用Aβ刺激原代小鼠小胶质细胞培养，以量化细胞因子、神经毒素或Aβ吞噬的分泌。用FK506或tat-VIVIT通过微渗透泵皮下处理转基因AD小鼠模型APP/PS1，量化其对细胞因子、小胶质细胞增生、斑块负荷和记忆的影响。Western blot分析证实了多种NFAT亚型在小鼠小胶质细胞中的表达。在没有或存在NFAT抑制剂FK506和tat-VIVIT的情况下，用Aβ原纤维刺激小胶质细胞培养，证明NFAT活性调节Aβ吞噬、神经毒素分泌和细胞因子分泌。将FK506和tat-VIVIT传递给转基因APP/PS1小鼠，可降低脾脏的细胞因子水平，但不影响脑细胞因子水平。然而，与对照组相比，FK506和tat-VIVIT显著减轻了治疗小鼠的小胶质瘤和Aβ斑块负荷。令人惊讶的是，通过t迷宫测试，这与记忆表现的变化无关。我们的研究结果表明，特异性NFAT抑制剂的开发可能为减轻AD中发生的小胶质细胞增生和Aβ斑块沉积提供了有效的策略。本文的在线版本（doi:10.1186/s12974-015-0255-2）包含补充材料，可供授权用户使用。
Amyloid β (Aβ) peptide is hypothesized to stimulate microglia to acquire their characteristic proinflammatory phenotype in Alzheimer’s disease (AD) brains. The specific mechanisms by which Aβ leads to microglial activation remain an area of interest for identifying attractive molecular targets for intervention. Based upon the fact that microglia express the proinflammatory transcription factor, nuclear factor of activated T cells (NFAT), we hypothesized that NFAT activity is required for the Aβ-stimulated microgliosis that occurs during disease. Primary murine microglia cultures were stimulated with Aβ in the absence or presence of NFAT inhibitors, FK506 and tat-VIVIT peptide, to quantify secretion of cytokines, neurotoxins, or Aβ phagocytosis. A transgenic mouse model of AD, APP/PS1, was treated subcutaneously via mini-osmotic pumps with FK506 or tat-VIVIT to quantify effects on cytokines, microgliosis, plaque load, and memory. Expression of various NFAT isoforms was verified in primary murine microglia through Western blot analysis. Microglial cultures were stimulated with Aβ fibrils in the absence or presence of the NFAT inhibitors, FK506 and tat-VIVIT, to demonstrate that NFAT activity regulated Aβ phagocytosis, neurotoxin secretion, and cytokine secretion. Delivery of FK506 and tat-VIVIT to transgenic APP/PS1 mice attenuated spleen but not brain cytokine levels. However, FK506 and tat-VIVIT significantly attenuated both microgliosis and Aβ plaque load in treated mice compared to controls. Surprisingly, this did not correlate with changes in memory performance via T-maze testing. Our findings suggest that development of specific NFAT inhibitors may offer promise as an effective strategy for attenuating the microgliosis and Aβ plaque deposition that occur in AD. The online version of this article (doi:10.1186/s12974-015-0255-2) contains supplementary material, which is available to authorized users.
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影响因子：
3.8
作者：
Fisher, Wayne G.;Yang, Pei-Chi;Medikonduri, Ram K.;Jafri, M. Saleet
通讯作者：
Jafri, M. Saleet
DOI：
10.1523/jneurosci.1064-09.2009
发表时间：
2009-10-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Abdul HM;Sama MA;Furman JL;Mathis DM;Beckett TL;Weidner AM;Patel ES;Baig I;Murphy MP;LeVine H 3rd;Kraner SD;Norris CM
通讯作者：
Norris CM
影响因子：
2.9
作者：
HAGA, S;IKEDA, K;ISHII, T
通讯作者：
ISHII, T
影响因子：
16
作者：
Aramburu, J;Garcia-Cozar, F;Hogan, PG
通讯作者：
Hogan, PG
影响因子：
64.5
作者：
Graef, IA;Wang, F;Crabtree, GR
通讯作者：
Crabtree, GR