Blood–Brain Barrier (BBB)-Permeable Ethanolamine-Type Plasmalogens 18:0/20:4 (PE-PLS 18:0/20:4) Ameliorate Cognitive Impairments in Aged Mice

Background: Plasmalogens (PLS) are a distinctive class of glycerophospholipids with reported neuroprotective properties; however, the mechanisms underlying their potential benefits for age-related cognitive decline remain incompletely understood. Methods: A D-galactose-induced mouse model of aging was used to evaluate the effects of PLS on cognitive performance. Hippocampal synaptic remodeling was assessed by examining the expression of synaptic proteins and receptors. An in vitro BBB model was used to evaluate the transport of PE-PLS 18:0/20:4. Molecular interaction analyses were conducted to investigate the potential binding of PE-PLS 18:0/20:4 to the brain-derived neurotrophic factor (BDNF) and its association with BDNF/TrkB signaling activation. Results: High-dose PLS supplementation significantly improved spatial memory and novel object recognition in D-galactose-treated mice. Molecular interaction analysis indicated that PE-PLS 18:0/20:4 could interact with BDNF through multiple hydrogen bonds. This interaction was associated with activation of the BDNF/TrkB signaling pathway, increased synaptic protein expression, and neuroprotective effects. Conclusions: PLS may mitigate age-related cognitive dysfunction by promoting hippocampal synaptic remodeling. PE-PLS 18:0/20:4 may contribute to these effects through BBB transport and modulation of BDNF/TrkB signaling, supporting the potential of plasmalogens as a nutritional strategy for promoting healthy brain aging.