Tan Yejun, Tang Wang, Xiao Wenbiao, Huang Roujie, Li Xin, Peng Weijun, Yan Kuipo, Cao Yuan, Zeng Yi, Kang Jin
Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
School of Mathematics, University of Minnesota Twin Cities, Minneapolis, MN, United States.
Front Aging Neurosci. 2023 Feb 16;15:1105690. doi: 10.3389/fnagi.2023.1105690. eCollection 2023.
Alzheimer's disease (AD) is the most common form of dementia characterized by a prominent cognitive deterioration of sufficient magnitude to impair daily living. Increasing studies indicate that non-coding RNAs (ncRNAs) are involved in ferroptosis and AD progression. However, the role of ferroptosis-related ncRNAs in AD remains unexplored.
We obtained the intersection of differentially expressed genes in GSE5281 (brain tissue expression profile of patients with AD) from the GEO database and ferroptosis-related genes (FRGs) from the ferrDb database. Least absolute shrinkage and selection operator model along with weighted gene co-expression network analysis screened for FRGs highly associated with AD.
A total of five FRGs were identified and further validated in GSE29378 (area under the curve = 0.877, 95% confidence interval = 0.794-0.960). A competing endogenous RNA (ceRNA) network of ferroptosis-related hub genes (, , , and ) was subsequently constructed to explore the regulatory mechanism between hub genes, lncRNAs and miRNAs. Finally, CIBERSORT algorithms were used to unravel the immune cell infiltration landscape in AD and normal samples. M1 macrophages and mast cells were more infiltrated whereas memory B cells were less infiltrated in AD samples than in normal samples. Spearman's correlation analysis revealed that LRRFIP1 was positively correlated with M1 macrophages ( = -0.340, < 0.001) whereas ferroptosis-related lncRNAs were negatively correlated with immune cells, wherein miR7-3HG correlated with M1 macrophages and , and correlated with memory B cells (|| > 0.3, < 0.001).
We constructed a novel ferroptosis-related signature model including mRNAs, miRNAs and lncRNAs, and characterized its association with immune infiltration in AD. The model provides novel ideas for the pathologic mechanism elucidation and targeted therapy development of AD.
阿尔茨海默病（AD）是最常见的痴呆形式，其特征是显著的认知功能衰退，严重程度足以损害日常生活。越来越多的研究表明，非编码RNA（ncRNAs）参与铁死亡和AD的进展。然而，铁死亡相关ncRNAs在AD中的作用仍未被探索。
我们获取了来自GEO数据库的GSE5281（AD患者脑组织表达谱）中差异表达基因与来自ferrDb数据库的铁死亡相关基因（FRGs）的交集。采用最小绝对收缩和选择算子模型以及加权基因共表达网络分析筛选出与AD高度相关的FRGs。
共鉴定出5个FRGs，并在GSE29378中进一步验证（曲线下面积=0.877，95%置信区间=0.794-0.960）。随后构建了铁死亡相关枢纽基因（、、、和）的竞争性内源性RNA（ceRNA）网络，以探索枢纽基因、lncRNAs和miRNAs之间的调控机制。最后，使用CIBERSORT算法揭示AD和正常样本中的免疫细胞浸润情况。与正常样本相比，AD样本中M1巨噬细胞和肥大细胞浸润更多，而记忆B细胞浸润更少。Spearman相关性分析显示，LRRFIP1与M1巨噬细胞呈正相关（=-0.340，<0.001），而铁死亡相关lncRNAs与免疫细胞呈负相关，其中miR7-3HG与M1巨噬细胞相关，和与记忆B细胞相关（||>0.3，<0.001）。
我们构建了一个新的包括mRNA、miRNA和lncRNA的铁死亡相关特征模型，并表征了其与AD中免疫浸润的关联。该模型为AD的病理机制阐明和靶向治疗开发提供了新的思路。
