Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems.
Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems.
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DOI：
10.1186/s12974-022-02459-1
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发表时间：
2022-04-23
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病(AD)是一种进行性神经退行性疾病，全球有近4亿人受到影响。淀粉样β蛋白(Aβ)在大脑中的积聚在历史上与阿尔茨海默病有关，最近的证据表明神经炎症在其发生和发展中起着核心作用。这些观察结果提出了一种理论，即Aβ是AD的主要触发因素，并诱导免疫脑细胞(即小胶质细胞)的促炎激活，最终导致神经元损伤和认知能力下降。为了验证这一假设，已经建立了许多体外系统来研究Aβ介导的天然免疫细胞的激活。然而，这些模型与AD大脑中的小胶质细胞的转录相似性从未在全基因组范围内进行过全面的研究。我们使用Bulk RNA-seq来评估用于模拟AD神经炎症的体外细胞类型之间的转录差异，包括几个已建立的、原代和IPSC来源的免疫细胞系(巨噬细胞、小胶质细胞和星形胶质细胞)，以及它们与AD大脑中的原始细胞的相似性。然后，我们分析了这些先天免疫细胞对合成的Aβ或脂多糖和干扰素γ的转录反应。我们发现，人诱导多能干细胞(HiPSC)来源的小胶质细胞(IMGL)是最类似于原代小胶质细胞的体外细胞模型。令人惊讶的是，合成Aβ在所分析的任何细胞模型中都没有引发强劲的转录反应，尽管测试了各种Aβ配方、浓度和处理条件。最后，我们发现细菌内毒素和干扰素γ激活小胶质细胞并诱导转录变化，这些变化类似于AD大脑中存在的疾病相关小胶质细胞(DAM)的转录图谱的许多方面，但不是全部。这些结果表明，对先天性免疫细胞培养的合成Aβ处理并不能概括AD大脑小胶质细胞中观察到的转录图谱。相反，用脂多糖和干扰素γ处理imgl引起的转录变化与在AD大脑中观察到的小胶质细胞相似。网上版载有补充材料，可在10.1186/s12974-022-02459-1查阅。
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aβ is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. We used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aβ or LPS and INFγ. We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aβ formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain. These results suggest that synthetic Aβ treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains. The online version contains supplementary material available at 10.1186/s12974-022-02459-1.
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影响因子：
6.2
作者：
Heng Y;Dubbelaar ML;Marie SKN;Boddeke EWGM;Eggen BJL
通讯作者：
Eggen BJL
DOI：
10.1177/1073858414530512
发表时间：
2015-04
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Gomez-Nicola D;Perry VH
通讯作者：
Perry VH
影响因子：
9.3
作者：
Das A;Kim SH;Arifuzzaman S;Yoon T;Chai JC;Lee YS;Park KS;Jung KH;Chai YG
通讯作者：
Chai YG
影响因子：
14
作者：
通讯作者：
--
影响因子：
168.9
作者：
Cagnin, A;Brooks, DJ;Banati, RB
通讯作者：
Banati, RB