Mar 14, 2024

Memory decline due to aging caused by a drastic decrease in a melatonin metabolite - Rikkyo University clarifies mechanism in mice



Specially Appointed Professor Atsuhiko Hattori of the Department of Sport and Wellness, College of Sport and Wellness, Rikkyo University, in collaboration with Assistant Professor Yusuke Maruyama and Professor Haruyasu Kato of the same department; Fellowship Researcher Kazuki Watanabe (Japan Society for the Promotion of Science (JSPS)) and Professor Jun Hirayama of Komatsu University; and Assistant Professor Hikaru Iwashita of Kansai Medical University, clarified that a drastic decrease in N1-acetyl-5-methoxykynuramine (AMK) in the hippocampus is one of the causes of memory decline related to aging. AMK is a melatonin metabolite in the brain involved in consolidation of short-term memories into long-term memories. The findings are expected to contribute to the development of a therapeutic drug for dementia.

The study was published on January 12, 2024 in the international academic journal, Journal of Pineal Research.
In a previous study in 2021, the research group revealed that the melatonin metabolite AMK, which is secreted from the pineal gland during night (thus closely related to sleep), has a much stronger effect in inducing long-term memory than melatonin. In the current study, the research group investigated whether a decreased AMK level in the hippocampus causes memory decline with aging.

To clarify synthesis of AMK in the hippocampus, the levels of melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK; the first-step metabolite of melatonin) and AMK (a metabolite synthesized from AFMK) in the pineal gland, plasma, and hippocampus were compared. The results revealed that melatonin secreted from the pineal gland reaches the hippocampus via the bloodstream and is subsequently converted to AMK in the hippocampus. Additionally, the group also investigated the genes for enzymes involved in AMK synthesis, identifying novel candidate genes.
In older mice, the AMK level in the hippocampus decreased to less than 1/20 of that in younger mice. At the same time, gene expression levels of enzymes involved in AMK synthesis significantly decreased with age. Additionally, administration of AMK induced phosphorylation of proteins known to be crucial for memory formation in the hippocampus. Furthermore, a comprehensive analysis of genes expressed in the hippocampus in older and younger mice revealed decreased expression of many genes involved in long-term memory formation in older mice. Based on these findings, it is suggested that a decrease in AMK levels may contribute to memory decline in old age in humans.

According to Hattori, "AMK or a potential new drug based on AMK holds promise as a memory-improving drug for impairment related to aging and for mild cognitive impairment (MCI), which is considered as a pre-stage of dementia. AMK may not only improve quality of life in older adults but may also be utilized for aging pets and in the training of police dogs and guide dogs. AMK is a substance that has great potential for future use."

Journal Information

  • Publication: Journal of Pineal Research
  • Title: N1-Acetyl-5-methoxykynuramine, which decreases in the hippocampus with aging, improves long-term memory via CaMKII/CREB phosphorylation
  • DOI: 10.1111/jpi.12934

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