Multi-omics integration reveals key miRNAs, immune inflammation, and signaling pathways in Alzheimer's disease:...

Alzheimer's disease (AD), a common neurodegenerative disorder, has unclear molecular mechanisms and therapeutic targets. In this study, multi-omics analysis and experimental validation were performed. By integrating three miRNA-seq, four differentially expressed miRNAs (miR-339-3p, miR-28-3p, miR-423-3p, miR-144-5p) were identified, closely related to synaptic function and immune-inflammatory responses. By integrating blood RNA-seq data, we found 725 mRNAs linked to AD, immune, and apoptosis pathways. Peripheral blood single-cell transcriptomics showed altered immune cell proportions in AD patients, indicating systemic immunodysregulation. Integrating the three omics datasets identified 388 key genes involved in JAK-STAT, PI3K-Akt, and MAPK pathways. Experimental validation showed that combining candidate miRNAs significantly reduced AD marker expression and promoted neuronal progenitor cell marker expression, but had limited effect on mature neuronal markers (MAP2, NeuN). However, providing a suitable neuronal environment could induce neuronal differentiation, showing neuronal induction potential. These findings reveal the dual role of synaptic dysfunction and neuroinflammation in AD progression, offering new insights into AD's molecular network and proposing a treatment framework combining immunomodulation and neuroregeneration.