Dietary Procyanidin C1 Improves Cognitive Function through MicroRNA-181a-5p

Procyanidin C1 (PC1), a trimer of (-)-epicatechin units found in cocoa, grapes, and apples, exhibits various health benefits. Nevertheless, its absorption rate is low, and the molecular mechanisms underlying biological regulation remain unknown. Here, we demonstrate how PC1 influences neural function and reveal a key regulator mediating these effects. Our results showed that PC1 improves spatial working memory and cognitive ability mediated by circulating microRNA(miR)-181a-5p. PC1 upregulates miR-181a-5p via the 67-kDa laminin receptor (67LR), which modulates brain-derived neurotrophic factor (BDNF) and its downstream signaling pathway. Furthermore, cognitive improvement, increased cyclic AMP-responsive element-binding protein (CREB) levels, extracellular signal-regulated kinase (ERK) phosphorylation, and upregulated BDNF in the hippocampus after oral PC1 gavage were entirely negated by miR-181a-5p inhibitor. This study provides mechanistic insights into how poorly absorbed dietary polyphenols modulate brain function, suggesting a previously unrecognized route by which gut-PC1-miRNA via 67LR signaling influences cognitive regulation.