Distinct and Overlapping Neuroprotective Efficacy of Silk Lutein and Sericin-Derived Oligopeptides from Yellow Silk Cocoons in Rodent Models of Aβ-Induced and Age-Related Cognitive Decline

Yellow silk cocoons of Bombyx mori provide two distinct bioactive classes: the carotenoid silk lutein (SL) and sericin-derived oligopeptides (SDOs). Their comparative efficacy and mechanisms in promoting cognitive health remain uncharacterized. This study compared the neuroprotective and cognitive-enhancing effects of SL and SDOs through chronic oral administration in two rodent models: an amyloid-beta (Aβ25–35)-induced amnesia model in mice and a natural aging model in rats. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests, and underlying mechanisms were investigated via in vivo hippocampal long-term potentiation (LTP) and immunohistochemical analysis for apoptosis markers. Both SL and SDOs significantly ameliorated Aβ-induced deficits in recognition and spatial memory. Both substances enhanced spatial memory and LTP in old male rats in the natural aging paradigm, with efficacy comparable to that of donepezil (Don). This LTP-enhancing effect was sex-specific, being prominent in males but absent in aged females, although both sexes showed improved recognition memory. Critically, cognitive impairments in the Aβ model were not associated with significant neuronal apoptosis, and the protective effects appeared independent of anti-apoptotic pathways. In conclusion, SL and SDOs are potent cognitive-enhancing agents that mitigate memory deficits in acute neurotoxicity and chronic aging models. Their primary mechanism appears to be a robust enhancement of hippocampal synaptic plasticity rather than apoptosis prevention, positioning them as powerful synaptoprotective agents. These findings validate the potential to upcycle this agro-industrial byproduct into high-value nutraceuticals for promoting healthy brain aging.