Characterization of a Bovine Serum Albumin‐Derived Pro‐Cognitive Peptide ( <scp>bSAPP</scp> ): An Orally Active Peptide Alleviates Cognitive Decline in <scp>HFD</scp> ‐Fed Mice via <scp>CCK</scp> Signaling Through the Gut‐Brain Axis

The global prevalence and burden of dementia continue to rise, driven not only by an aging population but also by obesity associated with unhealthy dietary habits. From a Quality of Life (QoL) perspective, identifying naturally derived compounds that enhance cognitive function is increasingly encouraged alongside pharmaceutical interventions. In this study, we investigated the anti-dementia effects of a peptide derived from bovine serum albumin using high-fat diet (HFD)-fed mice. We first found that the enzymatic digest of bovine serum albumin could orally alleviate cognitive decline induced by HFD. Then, we confirmed the oral pro-cognitive effects of the peptide derived from the digest and the underlying mechanisms. The peptide had an EC₅₀ of 0.01 mg/kg BW/day. Therefore, we designated it bSAPP (bovine serum albumin-derived pro-cognitive peptide). The cognition-enhancing effects of bSAPP were blunted by an α7nAChR antagonist, suggesting that the pro-cognitive effect of bSAPP was mediated by acetylcholine signaling. Moreover, bSAPP became ineffective in the presence of a CCK1R antagonist as well as in CCK1R^-/- mice, highlighting the involvement of CCK1R signaling. Furthermore, bSAPP increased the number of BrdU-positive cells in the dentate gyrus of the hippocampus and upregulated hippocampal expression of VEGF and NGF in a CCK1R-dependent manner. Additionally, the cognitive benefits of bSAPP were nullified by a capsaicin pre-treatment. In summary, we observed that bSAPP could orally enhance cognitive function in HFD-fed mice through CCK1R signaling via the gut-brain axis, accompanied by facilitated hippocampal cell proliferation and involvement of acetylcholine signaling.