Journal Article Ppublish 4 citations
PubMed: 40232249 DOI: 10.1177/13872877251329583
Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model.
J Alzheimers Dis 105(2):550-572
Authors: Fatma Saaoud, Lu Liu, Keman Xu, Yifan Lu, Ying Shao, Mohammed Ben Issa, Xiaohua Jiang, Xianwei Wang, Xiaolei Liu, Michael Autieri, Sheng Wu, Juncheng Wei, Jun Yu, Rihab Bouchareb, Avrum Gillespie, Jin Jun Luo, Laisel Martinez, Roberto Vazquez-Padron, Jianxin Sun, Huaqing Zhao, Hong Wang, Domenico Pratico, Xiaofeng Yang
Affiliations
- 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.
- Section of Nephrology, Hypertension, and Kidney Transplantation, Department of Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
- Department of Neurology, Temple University, Philadelphia, PA, USA.
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
- Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
- Department of Biomedical Education and Data Sciences, Temple University, Philadelphia, PA, USA.
- Alzheimer's Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Abstract
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.
MeSH
Cells, Genes, Cell Plasticity, Alzheimer Disease, Brain, Pathology, Inflammasomes, Immunity