Pentapeptide WN5 targets the gut microbiota in alleviating Alzheimer’s disease pathologies

BACKGROUND: Antioxidant peptides have gained attention as potential therapeutic agents for Alzheimer’s disease (AD). The gut microbiota is also increasingly being recognized as central to AD progression and a potential therapeutic target for the disease. OBJECTIVE: Using a recently-identified antioxidant pentapeptide (Trp-Pro-Pro-Lys-Asn, WN5), we sort to test the hypothesis that dietary components could target the microbiota to inhibit Aβ aggregation and relieve AD-related cognitive impairments. METHOD: An Aβ42 aggregation cell model was employed to predict the ability of WN5 to inhibit Aβ aggregation. APP/PS1 mice were then used to explore the learning and memory-improving capacity of WN5 by targeting the gut microbiota. RESULTS: WN5 dose-dependently attenuated cellular Aβ-aggregation. Oral administration of WN5 (WN5_G) was associated with decreased microbial diversity and tended to impact the abundance of several major bacterial species associated with AD. The observed microbiota changes were significantly associated with reduced hippocampal Aβ aggregation (17.6±0.71 for WN5_G and 25.4±1.7 for the control group; p <  0.009) and improved cognitive performance. However, these observations were absent when WN5 was administered intraperitoneally (WN5_Ip). CONCLUSION: The results from this preliminary study suggested that WN5 could be useful in ameliorating AD-related symptoms via the gut-brain-axis and further emphasize the significance of the gut microbiota in AD.