همایش ملی بیوانفورماتیک ایران

صفحه اصلی / 4th international edition and 13th Iranian Conference on Bioinformatics

Astrocyte-Mediated Regulation of Neurogenesis in the Anterior Hippocampus of Alzheimer's Disease Patients

نویسندگان :

Sarvenaz Sahebekhtiari¹ Morteza Hadizadeh² Hamid Forootanfar³ Masoud Rezaei⁴ Alieh Ameri⁵ Mojtaba Shakibaie⁶

1- Kerman University of Medical Sciences 2- Kerman University of Medical Sciences 3- Kerman University of Medical Sciences 4- Kerman University of Medical Sciences 5- Kerman University of Medical Sciences 6- Kerman University of Medical Sciences

کلمات کلیدی :

Alzheimer's Disease،Neurogenesis،Astrocytes،Anterior Hippocampus،Single-cell RNA Sequencing

چکیده :

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss, particularly affecting the hippocampus, a key region for memory and emotional regulation. The anterior hippocampus plays a crucial role in neurogenesis—the generation of new neurons—which is disrupted in AD, contributing to cognitive impairments (Tobin and Musaraca, 2019). Understanding neurogenesis regulation is essential for developing potential treatments for AD, as restoring neurogenic processes could alleviate cognitive decline (Young, 2020). Astrocytes, a type of glial cell, are critical in neurogenesis by maintaining the neural stem cell niche, managing inflammation, and providing metabolic support (Medeiros and LaFerla, 2013). This study investigated astrocyte-specific contributions to neurogenesis in the anterior hippocampus of AD patients using trajectory analysis and protein interaction networks based on single-cell RNA sequencing (scRNA-seq) data. Methods and Materials: scRNA-seq data from the GSE175814 dataset, which includes samples from AD patients and age-matched controls, were used to characterize neurogenic processes in the anterior hippocampus. Seurat (v5.1.0) and Harmony packages facilitated UMAP visualization, clustering, and integration to identify major cell populations. Cell type annotation was performed with the ScType package. Astrocytes were selected for trajectory analysis due to their crucial role in neuroinflammation and metabolic support, significantly altered in AD. Trajectory analysis using Monocle3 package reconstructed cellular developmental paths, revealing differentiation trajectories between normal and AD astrocytes and the gene expression changes governing neurogenesis in AD. Differentially expressed genes (DEGs) identified from this astrocyte-specific analysis overlapped with known neurogenesis-regulating genes and were further analyzed using the STRING webserver. Ten hub genes identified using CytoHubba plugin in Cytoscape from Protein-Protein interaction, included STAT3, CDH1, FGF2, CXCL12, EGFR, HIF1A, IL1B, TGFB1, MET, and PTEN, which were studied for their regulatory roles in neurogenesis. Results: The study identified several disrupted pathways affecting neurogenesis in AD. The MAPK/ERK pathway, crucial for neural stem cell proliferation and differentiation, is impaired in AD due to dysregulation by factors such as FGF2 and EGFR (Zhu and Lee, 2002). The PI3K/AKT pathway, regulated by PTEN and influenced by growth factors, is also disrupted, compromising cell survival and proliferation (Long and Cheng, 2021). STAT3-mediated JAK-STAT signaling integrates cytokine signaling and neuroinflammation, exacerbating neurogenic impairment in AD (Rusek and Smith, 2023). The TGF-beta pathway, involving TGFB1, modulates neurogenesis and neuroprotection but is disrupted (Wyss-Coray, 2006), while the hypoxia response pathway regulated by HIF1A supports cellular adaptation to hypoxic conditions common in AD brains (March-Diaz and Lara-Ureña, 2021). Its perturbation further impairs neurogenesis. Key interactors such as CDH1, CXCL12, IL1B, and MET were identified as critical nodes in astrocyte-mediated neurogenesis regulation, shedding light on AD pathogenesis. Conclusion: This study emphasizes the role of astrocytes in regulating neurogenesis in the anterior hippocampus of AD patients. Restoring neurogenic processes through targeting astrocyte-mediated pathways offers potential therapeutic strategies to alleviate cognitive decline in AD. Trajectory analysis of astrocyte differentiation revealed dynamic gene expression changes related to neurogenesis and AD pathogenesis, supporting therapeutic approaches targeting astrocyte pathways to enhance neurogenesis and combat cognitive decline in AD.