Targeting brain health: Whey protein hydrolysate intervention enhances cognitive function in middle-aged mice

Neurodegeneration is most prevalent in the elderly, resulting in memory loss or even dementia, and it places a considerable strain on society and the economy. The hydrolysate from whey protein, a natural byproduct of cheese-making, exhibits potent bioactivity and thus can serve as a potential strategy to slow down neurological aging. This research aimed to ascertain the neuroprotective effect of the whey protein hydrolysate (WPH) against age-related memory decline and further explore the underlying mechanisms. Our results indicated that a high dose (100 mg/kg) of the WPH could improve the behavioral performance of middle-aged mice and adjust the morphology and organization of hippocampal cells. Moreover, WPH-treated mice showed decreased levels of inflammation and oxidative stress and considerably reduced levels of amyloid beta 1–42 (Aβ1-42) and AchE in brain tissue. Hippocampus proteomic analysis revealed that differentially expressed proteins were mainly related to Aβ plaque, neurogenesis, and cAMP signaling pathways, such as Mdk, Mff, Pde2a, and Chrm1. After 20 weeks of the WPH intervention, the gut microbiomes associated with SCFA production and gut homeostasis were increased in mice. Our study provided evidence supporting the WPH as a candidate for functional ingredients in preventing cognitive deficits.