Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model

作者：Fatma Saaoud, Lu Liu, Keman Xu, Yifan Lu, Ying Shao, M. Issa, Xiaohua Jiang, Xianwei Wang, Xiaolei Liu, Michael V. Autieri, Sheng Wu, Juncheng Wei, Jun Yu, Rihab Bouchareb, Avrum Gillespie, Jin Jun Luo, Laisel Martinez, Roberto I. Vázquez-Padrón, Jianxin Sun, Huaqing Zhao, Hong Wang, Domenico Praticò, Xiaofeng Yang · 发表于：Journal of Alzheimer s Disease · 年份：2025 · DOI：10.1177/13872877251329583 · 被引用次数：8 · 研究领域：Immune responses and vaccinations、Tryptophan and brain disorders、Immune cells in cancer

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 modulat...