Professor Shinshu University Kamiina-Gun, Nagano, Japan
Abstract: Natto, a traditional Japanese fermented soybean food, offers health-promoting properties beyond basic nutrition. In this study, we investigated the neuroprotective effects of natto-derived peptides on cognitive function and their underlying mechanisms. Oral administration of natto fermented for 18 h with Bacillus subtilis var. natto TTCC12 significantly improved memory and learning ability in senescence-accelerated prone 8 (SAMP8) mice after 14 weeks compared to boiled soybean-fed groups. Metabolomic analysis of plasma from rats after oral administration revealed that several peptides increased with peptide fraction of 18-hour fermented natto but not with that of 42-hour fermented natto. Among them, the dipeptide Gln-Gln (QQ) improved learning and memory in a scopolamine-induced memory impairment model. Furthermore, QQ administration increased the expression of brain-derived neurotrophic factor (BDNF) and choline acetyltransferase (ChAT) in the hippocampus, suggesting its involvement in natto's cognitive-enhancing effects. A blood-brain barrier (BBB) permeability assay using an in vitro BBB model demonstrated that QQ could cross the BBB. In behavioral tests, C57BL/6J mice receiving oral QQ (14 days) followed by scopolamine exhibited significant improvements in learning and memory in both the novel object recognition and passive avoidance tests, whereas amino acid Gln administration showed no effect. This indicates that QQ acts as a peptide rather than being degraded into amino acids. QQ administration also upregulated markers for neurons (NeuN), synaptic function (Synaptophysin and PSD95), and neurotrophic factors (BDNF) in the hippocampus. These findings suggest that QQ crosses the BBB, enhances hippocampal BDNF expression, and improves cognitive function by promoting neuronal health and synaptic plasticity. Natto-derived peptides such as QQ hold potential for preventing age-related cognitive decline.
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.jpg "Shigeru Katayama, PhD photo")