Molecular Mechanisms of Dietary Bioactive Peptides in Treating Alzheimer’s Disease and Mild Cognitive Impairment by Network Pharmacology and Molecular Docking Analysis

Emerging evidence suggests that bioactive peptides from various foods have therapeutic potentials in improving cognitive function in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We aimed to explore the characteristics of these peptides and their mechanisms on AD/MCI using a network pharmacology approach. We compiled a dataset of cognition-enhancing peptides from literatures and identified shared targets between these peptides and AD/MCI using Swiss Target Predication, PharmMapper, OMIM, GeneCards, TTD, and Drugbank databases. We then performed functional enrichment analysis and constructed a gene–gene interaction network to identify key hub targets. Additionally, we investigated the transcription factors (TFs) and microRNAs (miRNAs) regulating these hub genes. Molecular docking and dynamic simulations were performed using AutoDock Vina and GROMACS. We identified 59 cognition-enhancing oligopeptides, typically short and rich in arginine. These peptides were predicted to interact with 222 potential targets relevant to AD/MCI, with functional pathways mainly involving neuroactive ligand-receptor interactions and inflammation. We identified 15 hub targets, regulated by 144 TFs and 95 miRNAs. Notably, peptides containing the "Trp-Tyr" sequence demonstrated strong binding affinities to many hub targets, especially matrix metalloproteinase-9. The findings provided valuable insights into the molecular mechanisms through which bioactive peptides may act against AD/MCI and highlight the potential of network pharmacology for future exploration of bioactive peptides from natural foods.