Whey protein hydrolysate intervention ameliorates memory deficits in APP/PS1 mice: Unveiling gut microbe–short-chain fatty acid–brain axis

The intricate causes of Alzheimer's disease (AD) hinder effective, lasting treatment. Although the dietary modulation of the brain–gut axis was explored for AD therapy, the exact mechanism remains unclear. This study suggested that 140 days of the whey protein hydrolysate (WPH) intake could attenuate the AD pathologic symptoms in APP/PS1 transgenic mice via a bidirectional action of the gut microbe–SCFA (short-chain fatty acid)–brain axis. Behavioral tests demonstrated that high-dose WPH (WPH-H, 100 mg/kg body weight [bw]) improved passive and recognition memory in mice. Furthermore, WPH-H significantly reduced amyloid beta 1–42 (Aβ_1–42) levels in serum (p < .05) and brain (p < .001) while enhancing serum superoxide dismutase (SOD) activity (p < .01). Brain acetylcholinesterase (p < .01) activity and pro-inflammatory factors in serum were also reduced. Notably, WPH-H remodeled gut microbiota composition by increasing Dubosiella and decreasing Bacteroides and norank_f__Ruminococcaceae while stimulating SCFA production. Proteomics indicated that WPH enhanced neurotoxic Aβ autophagy, synaptogenesis, neurotransmitter delivery, and antioxidative stress response via regulated protein expression. Correlation analysis revealed strong links between modified gut microbiota, elevated SCFA levels, and hippocampal protein up-regulation (Atg4b, Nsfl1c, Tcf20, Nr2f1, and Trappc9) and down-regulation (Krt1). Overall, the amelioration of memory deficits in APP/PS1 mice through WPH-H consumption can be attributed to the interconnected interactions among gut microbes, SCFAs, and brain. Our study illuminated the intricate interplay between nutrition, gut health, and memory function, emphasizing WPH's potential in alleviating AD symptoms.