Li Huijun, Fan Yawei, Chen Chan, Xu Yuzhong, Wang Xiong, Liu Wei
Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Biochem Biophys Rep. 2025 Apr 28;42:102035. doi: 10.1016/j.bbrep.2025.102035. eCollection 2025 Jun.
Synaptic dysfunction and synapse loss occur in Alzheimer's disease (AD). The current study aimed to identify synaptic-related genes with diagnostic potential for AD.
Differentially expressed genes (DEGs) were overlapped with phenotype-associated module selected through weighted gene co-expression network analysis (WGCNA), and synaptic-related genes. The overlapped hub genes were further processed using machine learning algorithms, intersected with module gene from protein-protein interaction (PPI) network constructed with DEGs, to yield co-hub genes. The diagnostic potentials of the co-hub genes were examined by receiver operating characteristic (ROC) analysis. Correlation between co-hub genes with clinical features and immune cell infiltration was analyzed. Finally, the expression of co-hub genes was analyzed in several datasets and validated in AD transgenic mice.
A total of three co-hub genes were identified, including MAP1B, L1CAM, and GABBR2. GABBR2 showed area under the curve (AUC) values of 0.98, 0.81, and 0.88 in the training and two external validation datasets. GABBR2 was negatively correlate with beta- and gamma-secretase activities, and infiltration of natural killer T cells and effector memory CD8 T cells. Finally, GABBR2 was validated to be downregulated in AD transgenic mice, aligning with bioinformatic findings. GABBR2 overexpression in N2a/APP cells increased ADAM10 while decreased of BACE1, leading to upregulation of sAPPα while downregulation of sAPPβ.
In conclusion, GABBR2 acts as a novel biomarker for the diagnosis of AD and negatively correlated with Aβ in AD.
阿尔茨海默病（AD）中会出现突触功能障碍和突触丧失。本研究旨在鉴定具有AD诊断潜力的突触相关基因。
将差异表达基因（DEGs）与通过加权基因共表达网络分析（WGCNA）选择的表型相关模块以及突触相关基因进行重叠。使用机器学习算法对重叠的枢纽基因进行进一步处理，并与由DEGs构建的蛋白质-蛋白质相互作用（PPI）网络中的模块基因进行交集，以产生共同枢纽基因。通过受试者工作特征（ROC）分析来检验共同枢纽基因的诊断潜力。分析共同枢纽基因与临床特征和免疫细胞浸润之间的相关性。最后，在几个数据集中分析共同枢纽基因的表达，并在AD转基因小鼠中进行验证。
共鉴定出三个共同枢纽基因，包括MAP1B、L1CAM和GABBR2。在训练数据集和两个外部验证数据集中，GABBR2的曲线下面积（AUC）值分别为0.98、0.81和0.88。GABBR2与β-和γ-分泌酶活性以及自然杀伤T细胞和效应记忆CD8 T细胞的浸润呈负相关。最后，在AD转基因小鼠中验证了GABBR2表达下调，这与生物信息学结果一致。在N2a/APP细胞中过表达GABBR2可增加ADAM10，同时降低BACE1，导致sAPPα上调而sAPPβ下调。
总之,GABBR2作为AD诊断的新型生物标志物，在AD中与Aβ呈负相关。
