Multi-omics integration identifies CACNG3 as a synaptic calcium channel regulator in Alzheimer's disease: Mechanistic insights and therapeutic implications

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and impaired daily functioning. As its pathogenesis remains incompletely understood, integrated multi-omics analysis has become crucial for identifying key disease molecules, pathological mechanisms, and therapeutic targets. This study analyzed AD-related transcriptomic and proteomic profiles from human frontal cortex datasets. Using R software, we performed data normalization, weighted gene co-expression network analysis (WGCNA), and differential expression analysis, identifying 26 upregulated and 61 downregulated signature molecules. Functional enrichment, protein-protein interaction (PPI) network analysis, and machine learning revealed these molecules' significant enrichment in synaptic functions and Calcium Channel regulation, pinpointing 7 key molecules. Validation in independent datasets and AD mouse models consistently confirmed these findings at the mRNA and protein levels. Among them, the expression of CACNG3 was significantly decreased in multiple brain regions of AD patients. In addition, the molecule is closely related to the level of infiltration of a variety of neuroimmune cells (such as astrocytes and oligodendrocytes). We explored the function of CACNG3 in AD through cell experiments, suggesting that it may damage synaptic plasticity by regulating the calcium signaling pathway. This study provides a new perspective for further understanding the pathogenesis of AD and lays a theoretical foundation for the development of new therapeutic targets.

Alzheimer's disease; CACNG3; Calcium signaling; Synaptic plasticity.