Juvenal Guilherme, Meinerz Carine, Ayupe Ana Carolina, Campos Henrique Correia, Reis Eduardo Moraes, Longo Beatriz Monteiro, Pillat Micheli Mainardi, Ulrich Henning
Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, Brazil.
Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria-RS, Brazil.
Cell Biosci. 2024 Jun 18;14(1):82. doi: 10.1186/s13578-024-01251-3.
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.
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.
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.
神经祖细胞（NPCs）可从发育中的大脑中培养出来，重现神经发育过程中的许多进程。它们能从多种动物模型中分离得到，比如携带淀粉样前体蛋白（APP）以及早老素1和2（PSEN 1和2）突变的转基因小鼠，这些是家族性阿尔茨海默病（fAD）的特征。用炎症相关肽，如缓激肽（BK）及其拮抗剂HOE - 140来调节这些细胞的发育，有助于了解此类分子在相关AD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。为验证微阵列数据，对8个与AD免疫反应相关的重要基因进行了定量实时逆转录聚合酶链反应（RT - PCR），这些基因包括CCL12、CCL5、CCL3、C3、CX3CR1、TLR2、肿瘤坏死因子α以及Iba - 1。此外，对各处理组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分析、蛋白质 - 蛋白质相互作用网络的构建与分析，最后将我们的数据与AD患者的人类数据集进行比较。这些处理影响了主要与小胶质细胞介导的神经炎症反应相关的基因表达水平，BK促进了那些富集与免疫功能障碍、神经退行性变和细胞周期相关的进程、生物途径及细胞成分的基因表达增加。HOE - 140对B2受体的抑制导致该系统中AD相关异常的减少。
BK是一种重要的免疫调节剂，可增强在携带AD遗传负荷的转基因神经球中所发现的免疫变化。缓激肽处理可调节与小胶质细胞介导的神经炎症相关的基因表达率。在阿尔茨海默病中抑制缓激肽活性可能会减缓疾病进展。
