缓激肽可促进携带 APPswe 和 PS1dE9 突变的分化胚胎神经球的免疫反应。

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell and Bioscience Pub Date : 2024-06-18 DOI:10.1186/s13578-024-01251-3
Guilherme Juvenal, Carine Meinerz, Ana Carolina Ayupe, Henrique Correia Campos, Eduardo Moraes Reis, Beatriz Monteiro Longo, Micheli Mainardi Pillat, Henning Ulrich
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引用次数: 0

摘要

背景:神经祖细胞(NPC)可以从发育中的大脑中培养出来,重现神经发育过程中的许多过程。它们可以从多种动物模型中分离出来,例如携带淀粉样前体蛋白(APP)和预激蛋白 1 和 2(PSEN 1 和 2)突变的转基因小鼠,这些突变是家族性阿尔茨海默病(fAD)的特征。用缓激肽(BK)及其拮抗剂 HOE-140 等炎症相关肽调节这些细胞的发育,有助于了解这些分子在相关阿尔茨海默病模型中的影响:我们对用 BK 和 HOE-140 处理的转基因神经球进行了全基因表达分析。为了验证芯片数据,我们对 8 个与 AD 免疫反应相关的重要基因,如 CCL12、CCL5、CCL3、C3、CX3CR1、TLR2 和 TNF alpha 以及 Iba-1 进行了定量实时反转录聚合酶链反应(RT-PCR)。此外,我们还对不同治疗之间的转录谱进行了比较分析,包括基因本体和反应组富集、蛋白质-蛋白质相互作用网络的构建和分析,最后还将我们的数据与来自AD患者的人类数据集进行了比较。治疗影响了主要与小胶质细胞介导的神经炎症反应有关的基因的表达水平,其中BK促进了与免疫功能障碍、神经变性和细胞周期有关的过程、生物通路和细胞成分的基因表达。通过HOE-140抑制B2受体可减少该系统引起的AD相关异常:结论:BK 是一种重要的免疫调节剂,能增强携带 AD 遗传负荷的转基因神经球中发现的免疫学变化。缓激肽治疗可调节小胶质细胞介导的神经炎症相关基因的表达率。抑制缓激肽在阿尔茨海默病中的活性可能会减缓疾病的进展。
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Bradykinin promotes immune responses in differentiated embryonic neurospheres carrying APPswe and PS1dE9 mutations.

Background: Neural progenitor cells (NPCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated from a variety of animal models, such as transgenic mice carrying mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN 1 and 2), characteristic of familial Alzheimer's disease (fAD). Modulating the development of these cells with inflammation-related peptides, such as bradykinin (BK) and its antagonist HOE-140, enables the understanding of the impact of such molecules in a relevant AD model.

Results: We performed a global gene expression analysis on transgenic neurospheres treated with BK and HOE-140. To validate the microarray data, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed on 8 important genes related to the immune response in AD such as CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF alpha and Iba-1. Furthermore, comparative analysis of the transcriptional profiles was performed between treatments, including gene ontology and reactome enrichment, construction and analysis of protein-protein interaction networks and, finally, comparison of our data with human dataset from AD patients. The treatments affected the expression levels of genes mainly related to microglia-mediated neuroinflammatory responses, with BK promoting an increase in the expression of genes that enrich processes, biological pathways, and cellular components related to immune dysfunction, neurodegeneration and cell cycle. B2 receptor inhibition by HOE-140 resulted in the reduction of AD-related anomalies caused in this system.

Conclusions: BK is an important immunomodulatory agent and enhances the immunological changes identified in transgenic neurospheres carrying the genetic load of AD. Bradykinin treatments modulate the expression rates of genes related to microglia-mediated neuroinflammation. Inhibiting bradykinin activity in Alzheimer's disease may slow disease progression.

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来源期刊
Cell and Bioscience
Cell and Bioscience BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
10.70
自引率
0.00%
发文量
187
审稿时长
>12 weeks
期刊介绍: Cell and Bioscience, the official journal of the Society of Chinese Bioscientists in America, is an open access, peer-reviewed journal that encompasses all areas of life science research.
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