Background: Early brain growth demands essential precursors and nutrients. Lactoferrin (LF), a sialylated iron-binding glycoprotein rich in sialic acid (Sia) residues on its N-glycans, is significantly more abundant in human milk than in cow milk-based formulas. Sia forms polysialic acid (polySia), primarily attached to neural cell adhesion molecule (NCAM), producing polySia–NCAM, a key neuroplasticity marker involved in brain remodelling, neurogenesis, and cognition. Despite evidence linking LF to neurodevelopment and cognitive support (1), the specific effects of iron saturation and sialylation within LF on these outcomes remain unclear.
Methods: Lactating Wistar rat dams were fed standard diets supplemented with native bovine LF (Native-bLF), iron-depleted LF (Apo-LF), or Sia-depleted LF (Desia-LF) at 0.60 g/kg throughout lactation. From postnatal day 22, dams and offspring received standard chow and water ad libitum. Offspring underwent the behavioural assessments between postnatal days 44 and 59. PolySia–NCAM expression (2) in the hippocampus was evaluated qualitatively by Western blot on day 63. The protocol was approved by the Xiamen University Animal Ethics Committee (AE1640102).
Results: Behavioural assessments demonstrated that offspring exposed to Apo-LF exhibited reduced anxiety-like behaviour in the open field test (p < 0.05). In the Morris water maze, Apo-LF offspring showed enhanced spatial learning, evidenced by significantly shorter escape latencies during the 9-day training period compared to both Native-LF and Desia-LF groups (p < 0.02). In contrast, Desia-LF offspring showed the poorest cognitive performance, although escape latency and anxiety-like behaviour did not differ significantly between Desia-LF and Native-LF groups (p > 0.05). Apo-LF supplementation also significantly increased polySia-NCAM expression in the hippocampus compared to the Native-LF group (p = 0.033), whereas no significant difference was observed between Desia-LF and Native-LF groups (p > 0.05).
Conclusion: Maternal lactoferrin supplementation during lactation enhances cognitive development by modulating synaptic structure and plasticity, thereby shaping neurodevelopmental outcomes through distinct molecular mechanisms, with sialylation playing a crucial role in neuroplasticity.