Peripheral Choroid/RPE/Sclera as a Shared Pathogenic Hub: Multi-Tissue Transcriptomic Profiling Identifies Common...

Age-related macular degeneration (AMD) and Alzheimer's disease (AD), two prevalent neurodegenerative disorders, share overlapping pathophysiological features yet lack cross-disease therapeutic strategies. This study systematically investigates their parallel genes and shared molecular mechanisms to identify potential therapeutic targets for dry AMD, a condition with limited treatment options.

Transcriptomic datasets for AMD (GSE155154) and AD (GSE95587) were retrieved from the GEO database. AMD tissues were stratified into four subgroups: macular retina (MR), macular choroid/RPE/sclera (MCRS), peripheral retina (PR), and peripheral choroid/RPE/sclera (PCRS). Common differentially expressed genes (DEGs) were identified and analyzed via functional enrichment (GO, KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks. Drug-gene interactions and competing endogenous RNA (ceRNA) networks were constructed to prioritize therapeutic targets. Key hub genes were experimentally validated in a sodium iodate-induced AMD murine model using RT-qPCR.

Comparative analysis revealed 89, 56, 4, and 130 common DEGs between AD and MR, MCRS, PR, and PCRS subgroups, respectively. Neuroactive ligand-receptor interactions were prioritized in MR/MCRS-AD analyses, while extracellular matrix organization emerged as the dominant pathway in PCRS-AD comparisons. GSEA identified conserved the TNFα signaling pathway via NF-κB across both diseases. PCRS exhibited consistent expression trends for shared genes and pathways with AD. Computational screening prioritized seven druggable targets (COL1A1, COL1A2, COL3A1, MMP2, MMP9, VCAN, ITGA5) with dual therapeutic potential, along with a reconstructed circRNA (circRNA_002179)-miRNA (miR-124)-mRNA (VCAN) regulatory axis. Experimental validation in a sodium iodate-induced AMD murine model confirmed region-specific dysregulation: hub genes were significantly downregulated in MCRS but upregulated in PCRS.

Our study delineates both convergent and divergent molecular landscapes of AMD and AD, with PCRS emerging as a critical locus for shared pathophysiology. These findings bridge a critical gap in understanding AMD-AD comorbidity, offering actionable strategies for targeted drug development.