**1. Introduction**

The rapid growth of aging populations worldwide is associated with an increased incidence of cognitive decline and dementia that become a growing burden not only on patients and their families but also on national healthcare systems. Due to the lack of effective dementia therapies, increasing attention is given to preventive approaches. Recent epidemiological studies suggest that the consumption of certain dairy products reduces the risk of cognitive decline in the elderly and may prevent Alzheimer's disease [1].

Crichton et al. [2] reported that individuals who consumed low-fat dairy products, including yogurt and cheese, once a week had a higher cognitive function than those who did not. A survey-based study of self-reported health information showed that the consumption of low-fat dairy products was associated with increased memory recall, increased social functioning, and decreased stress [3,4]. Ozawa et al. [3,4] surveyed more than 1000 Japanese subjects who were living in the community, aged 60–79 years, and free from dementia to investigate their dietary patterns and any potential association with a reduced risk of dementia symptoms. The authors concluded that including milk or fermented dairy products in the diet reduces the risk of dementia in the general Japanese population. In a clinical trial, Ogata et al. [5] investigated the association between the intake of dairy products and short-term memory and found that the intake of dairy products is highly associated with improved short-term memory. It has also been demonstrated that the intake of dairy products fermented with *Penicillium candidum*, i.e., Camembert cheese, had preventive effects on Alzheimer's disease pathology in a mouse model [6].

We have previously identified tryptophan-tyrosine (WY)-related peptides, including the β-lactopeptide of glycine-threonine-tryptophan-tyrosine (GTWY) peptide, β-lactolin, derived from β-lactoglobulin in an enzymatic whey protein digest [7]. The β-lactolin was smoothly absorbed into the body and delivered to the brain where it was associated with a dopamine level increase, resulting in improved spatial and object memory [7]. In addition, we demonstrated that whey peptides rich in WY-related peptides improved memory and attention in a clinical trial [8]. These reports suggested that WY-related peptides improve cognitive function. However, whether and how the WY dipeptide, the core sequence of WY-related peptides, improves cognitive function has not been investigated. The gap in our knowledge about the pharmacological effects of the WY dipeptide on memory impairment hinders the assessment of the underlying mechanism of the effect of whey peptide preparations rich in WY-related peptides on cognitive performance in clinical trials.

In the present study, we examined the effects of tryptophan-containing dipeptides, including the WY dipeptide, on memory impairment and their mechanisms.
