Saaoud Fatma, Liu Lu, Xu Keman, Lu Yifan, Shao Ying, Ben Issa Mohammed, Jiang Xiaohua, Wang Xianwei, Liu Xiaolei, Autieri Michael, Wu Sheng, Wei Juncheng, Yu Jun, Bouchareb Rihab, Gillespie Avrum, Luo Jin Jun, Martinez Laisel, Vazquez-Padron Roberto, Sun Jianxin, Zhao Huaqing, Wang Hong, Pratico Domenico, Yang Xiaofeng
Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA.
Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
J Alzheimers Dis. 2025 May;105(2):550-572. doi: 10.1177/13872877251329583. Epub 2025 Apr 15.
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment. Neuroinflammatory processes, mediated by glial and immune cells, contribute to neuronal damage. Emerging evidence implicates innate immune mechanisms, including trained immunity and cell trans-differentiation, in AD pathogenesis, though their roles remain unclear.ObjectiveTo investigate transcriptomic changes in the 3xTg-AD mouse model, focusing on trained immunity and cell trans-differentiation in disease mechanisms.MethodsRNA-sequencing was performed on brain tissue (cortex plus hippocampus) from 11-month-old female 3xTg-AD and wild-type mice (n = 3/group). Differentially expressed genes (fold change > 1.5, p < 0.05) were identified and followed by bioinformatics and knowledge-based transcriptomic profiling. Public AD datasets were also analyzed.Results3xTg-AD mice exhibited 316 upregulated and 412 downregulated genes. Downregulated genes included those for blood-brain barrier protein, while upregulated genes related to cerebrospinal fluid. Increased expression of proinflammatory markers, as well as genes related to cell differentiation, proliferation, activation, and adhesion. Upregulation of genes associated with cell migration and trans-differentiation suggests a potential role for inflammation and cellular plasticity. Additionally, genes involved in inflammasome pathways, immunometabolism, and trained immunity were upregulated. Mechanistically, these genes were modulated by knockdown of trained immunity promoter SET-7, overexpression of trained immunity inhibitor IL-37, and knockout of inflammasome genes IL-1 receptor, caspase-1, and pattern recognition receptor CD36.ConclusionsThe finding underscore the potential role of trained immunity and cell trans-differentiation in AD, revealing a mechanistic framework in which danger-associated molecular patterns drive innate immune responses, inflammasome activation, and cell plasticity contribute to AD, offering therapeutic targets for neuroinflammation and cellular reprograming.
背景
阿尔茨海默病（AD）是一种以记忆障碍为特征的神经退行性疾病。由胶质细胞和免疫细胞介导的神经炎症过程会导致神经元损伤。新出现的证据表明，包括训练免疫和细胞转分化在内的先天免疫机制参与了AD的发病过程，但其作用仍不明确。
目的
研究3xTg-AD小鼠模型中的转录组变化，重点关注疾病机制中的训练免疫和细胞转分化。
方法
对11月龄雌性3xTg-AD小鼠和野生型小鼠（每组n = 3）的脑组织（皮质加海马体）进行RNA测序。鉴定差异表达基因（倍数变化> 1.5，p < 0.05），随后进行生物信息学和基于知识的转录组分析。还分析了公开的AD数据集。
结果
3xTg-AD小鼠表现出316个基因上调和412个基因下调。下调的基因包括血脑屏障蛋白相关基因，而上调的基因与脑脊液相关。促炎标志物以及与细胞分化、增殖、激活和黏附相关的基因表达增加。与细胞迁移和转分化相关的基因上调表明炎症和细胞可塑性可能发挥作用。此外，参与炎性小体途径、免疫代谢和训练免疫的基因上调。从机制上讲，这些基因受到训练免疫启动子SET-7敲低、训练免疫抑制剂IL-37过表达以及炎性小体基因IL-1受体、半胱天冬酶-1和模式识别受体CD36敲除的调节。
结论
这些发现强调了训练免疫和细胞转分化在AD中的潜在作用，揭示了一个机制框架，其中危险相关分子模式驱动先天免疫反应、炎性小体激活，细胞可塑性导致AD，为神经炎症和细胞重编程提供了治疗靶点。
