Tyr-Pro – A dipeptide derived from soybeans can improve the memory


In a study that could help one day give a literal meaning to food for thought, researchers from Kyushu University in Japan have reported that a protein fragment that makes its way into the brain after being ingested can reduce memory degradation in mice treated to simulate Alzheimer’s disease.

Derived by breaking apart the proteins in soybeans, the memory-effecting molecule is classified as a dipeptide because it contains just two of the protein building blocks known as amino acids.

Unique about the dipeptide used in the study is that it is currently the only one known to make the trip from a mouse’s stomach to its brain intact despite the odds against it.

“On top of the possibility of being broken down during digestion, peptides then face the challenge of crossing a highly selectively barrier to get from the blood into the brain,” says Toshiro Matsui, professor in the Faculty of Agriculture at Kyushu University and leader of the study published in npj Science of Food.

“While our previous studies were the first to identify a dipeptide able to make the journey, our new studies now show that it can actually affect memory in mice.”

Working in collaboration with researchers at Fukuoka University, the researchers investigated the effects of the dipeptide–named Tyr-Pro because it consists of the amino acids tyrosine and proline–by feeding it to mice for several days before and after injecting them with a chemical that is commonly used to simulate Alzheimer’s disease by impairing memory functions.

In tests to evaluate short-term memory by comparing a mouse’s tendency to explore different arms of a simple maze, impaired mice that had ingested the dipeptide over the past two weeks fared better than those that had not, though both groups were overall outperformed by mice without induced memory impairment.

The same trend was also found in long-term memory tests measuring how long a mouse stays in the lighted area of an enclosure to avoid a mild electrical shock experienced in the dark area after having been trained in the box a day before.

Though there have been other reports suggesting some peptides can reduce the decline of brain functions, this is the first case where evidence also exists that the peptide can enter the brain intact.

“We still need studies to see if these benefits carry over to humans, but we hope that this is a step toward functional foods that could help prevent memory degradation or even improve our memories,” comments Matsui.

In a recent study, we provided strong evidence that dipeptides possessing Pro, such as Gly-Pro and Tyr-Pro, can be transported across the blood–brain barrier (BBB) in an intact form into the parenchyma of peptide-perfused mouse brain1.

Thus far, several animal reports have hinted at the memory-improving effect of peptides, such as Leu-His, which attenuates microglial activation and emotional disturbances2, Met-Lys-Pro3, and Trp-Tyr4, which prevent cognitive decline.

In the report of administered Trp-[carboxyl-14C]Tyr4, radioactive substances were detected in mouse brain, while no evidence on accumulation of the intact dipeptide in the brain parenchyma was provided.

In contrast, using our proposed phytic acid-aided MALDI-MS/MS imaging analysis1,5, we pointed out the first finding that the BBB-transportable Tyr-Pro from soybean hydrolysate1 subsequently accumulated in the hippocampus, cerebral cortex, hypothalamic area, striatum, and cerebellum of mouse brain.

The accumulated regions mainly regulate memory6; therefore, in vivo experiments using memory-impaired mice will provide insight into the benefits of BBB-transportable Tyr-Pro against cognitive impairment.

Amyloid β peptide (Aβ)25-35-induced mice were used for this study, since the Aβ25-35-induction was confirmed to cause the impairment of cognitive brain function7,8.

All the animal procedures were performed in accordance with the National Institutes of Health guidelines for the use of experimental animals.

The experimental protocol was reviewed and approved by the Animal Studies Committee of Nihon Bioresearch Inc. (Study No. 390066, Gifu, Japan). Five-week-old male ddY mice with 23–28 g body weight (Japan SLC Inc., Shizuoka, Japan) were used in this study.

The experimental schedules are shown as Fig. ​Fig.1a.1a. Tyr-Pro (100 mg/kg) was orally administered twice a day for 16 days, except for days of i.c.v. injection of Aβ25–35 peptide and behavioural tests (Tyr-Pro administration once a day).

The mice received i.c.v. injection of Aβ25–35 peptide at 6 nmol/mouse on the 7th day and Tyr-Pro administration was performed after recovery from anaesthesia, according to a previous report with several modifications15. Spontaneous alternation performance (Y-maze test) was started at 60 min after Tyr-Pro administration on the 14th day.

Passive avoidance test (acquisition trial on the 15th day and retention trial on the 16th day) was started at 60 min after Tyr-Pro administration on each day. After the passive avoidance test, hippocampus and cerebral cortex of mouse brain were taken and stored at −80 °C until analysis. Other detail methods are available in supplemental information.

Kyushu University


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