Catechins in insomnia-Alzheimer's disease comorbidity: A network pharmacology and molecular docking study

The comorbidity of insomnia and Alzheimer's disease (AD) is strongly driven by the interplay between circadian rhythm disruption and immune dysfunction. Catechins are multi-target polyphenols capable of modulating both processes, yet their precise mechanism of action remains elusive. Insomnia and AD related differentialy expressed target genes were specifically sourced from circadian rhythm and immune phenotypes. Two machine learning algorithms were then applied to refine and identify the pivotal targets from this phenotype-driven target pool. Functional enrichment analyses, including kyoto encyclopedia of genes and genomes and gene set enrichment analysis, were performed to elucidate the involved signaling pathways. The compound-comorbidity differentialy expressed target genes related to circadian and immunity network identified catechin (C) and epicatechin as core components. PED4D, HMOX1, and IGF1 were robustly identified as the pivotal targets. PDE4D was found to be centrally involved in the complement pathway. The complement pathway and the phosphatidylinositol 3-kinase/Akt signaling pathway were significantly enriched. This dual pathway regulation converges to govern microglia-mediated synaptic pruning, a process integral to both sleep and neurodegeneration. This study unveils a mechanistic link from core catechins to the regulation of synaptic pruning via circadian-immune crosstalk, offering a novel therapeutic perspective for the insomnia-AD comorbidity.