Bioavailability and mechanism of action of blood brain barrier transportable dipeptide Tyr-Pro for its therapeutic potential on cognitive impairment

抄録

【Introduction of speaker】

Education

Ph.D., College of Pharmaceutical Sciences, Zhejiang University, China, 2019

B.S., School of Pharmacy, He’nan University, China, 2014

Professional experience

Postdoctoral research, Zhejiang University, China, 2019-2021

JSPS Postdoctoral Fellowship, Kyushu University, Japan, 2021-2023

Assistant Professor, Tokyo Medical and Dental University, Japan, 2024-present

　Cognitive-related diseases such as Alzheimer's disease (AD) are well-known to markedly impair memory and negatively affect daily activities [1]. Numerous studies have elucidated the molecular mechanisms underlying the pathogenesis of AD such as cholinergic dysfunction, amyloid beta (Aβ) plaques, neurodegeneration, etc. To date, the most used drugs in the market for treating AD include acetylcholinesterase (AChE) inhibitors: tacrine, donepezil, etc. and N-methyl-D-aspartate receptor (NMDAR) antagonist: memantine [2]. However, they can only alleviate the symptom but not cure the disease. Therefore, an alternative strategy like consumption of brain-beneficial functional foods is urgently needed. In recent decades, peptides, as a well-known functional food exhibiting various physiological effects including beneficial effects on the brain, were widely studied [3]. However, the blood-brain barrier (BBB) strictly regulates the transport of substances into the brain. Before assessing their potential effects, it's crucial to ascertain whether candidate compounds can penetrate the BBB and reach their intended brain regions, as well as to elucidate the mechanism underlying physiological responses.

　Tyr-Pro, as a first recognized oral dipeptide that can across the BBB and improve impaired memory in Aβ-injected AD model mice, is potentially expected to be developed as an orally effective functional food [4-5]. However, the bioavailability of Tyr-Pro including the absorption into blood and accumulation into the brain after single oral administration and the detailed mechanism of action study regarding to cognitive impairment effect remain elusive. Therefore, in the present study, we demonstrate (1) whether Tyr-Pro can reach the brain parenchyma in an intact form after oral administration to mice [6] and (2) clarify the mechanism of action study of Tyr-Pro on acetylcholine (ACh) nervous system using NE-4C cells [7]. We provided the first evidence that Tyr-Pro can transport from the plasma to the brain parenchyma in intact form after oral administration to mouse and stimulate the ACh nervous system by AdipoR1-induced ChAT activation in NE-4C cells. We hope that our research can provide a new perspective for the prevention or treatment of AD, such as discovering more molecules capable of crossing the BBB or molecules with similar molecular mechanisms in the future.

References

[1] World Health Organization, 2021. [2] Ng Y. et al. Neurochem. Int. 89, 260(2015). [3] Li Z. et al. J. Agric. Food Chem 71, 5(2023) [4] Tanaka M. et al. Sci Rep 9, 5769(2019). [5] Tanaka M. et al. npj Sci Food 4, 7(2020). [6] Cheng L. et al. Sci Rep 13, 16908 (2023). [7] Cheng L. et al. J. Agric. Food Chem. 72, 13(2024).