Dementia is defined as the loss of cognitive functioning—including thinking, remembering, and reasoning—and is very prevalent in Japan. Currently, the treatment satisfaction for dementia is among the lowest and no drug therapy is available to cure the disease. With a rapidly ageing global population, the development of dementia preventive and therapeutic drugs is critical.
Cognitive impairment has been linked to the consumption of excess table salt, a ubiquitous food seasoning. High salt (HS) intake can also lead to hypertension. To prevent adverse health outcomes, the World Health Organization recommends limiting salt intake to less than 5 g per day. The involvement of angiotensin II (Ang II)—a hormone that plays a key role in regulating blood pressure and fluid balance—and its receptor “AT1”, as well as that of the physiologically important lipid molecule prostaglandin E2 (PGE2 and its receptor “EP1” in hypertension and neurotoxicity is well-recognized. However, the involvement of these systems in HS-mediated hypertension and emotional/cognitive impairment remains elusive.
To this end, a recent study published in the British Journal of Pharmacology thoroughly evaluated the aspects of HS-mediated hypertension and emotional/cognitive impairment. The study was performed by a team of collaborating researchers from Japan, and has shown how hypertension, mediated by the crosstalk between Ang II-AT1 and PGE2-EP1 causes emotional and cognitive dysfunction.
Author Hisayoshi Kubota from Fujita Health University’s Graduate School of Health Science comments, “Excessive salt intake is considered a risk factor for hypertension, cognitive dysfunction, and dementia. However, studies focusing on the interaction between the peripheral and central nervous system have not sufficiently investigated this association.”
According to the published data, the addition of excessive phosphates to the protein “tau” is primarily responsible for this emotional and cognitive consequences. The findings are particularly noteworthy because tau is a key protein of the Alzheimer's disease.
The team first loaded laboratory mice with an HS solution (2% NaCl in drinking water) for 12 weeks and monitored their blood pressure. “The effects of HS intake on emotional/cognitive function and tau phosphorylation were also examined in two key areas of the mouse brain—the prefrontal cortex and the hippocampus,” explains Prof. Mouri. Next, they also studied the involvement of the Ang II-AT1 and PGE2-EP1 systems in the HS-induced hypertension and neuronal/behavioral impairment.
The results were remarkable and encouraging: The brains of the experimental mice had several biochemical alternations. At the molecular level, besides the addition of phosphates to tau, the researchers also observed a decrease in the phosphate groups linked to a key enzyme called “CaMKII”—a protein involved in brain signaling. Moreover, changes in the levels of “PSD95”—a protein that plays a vital role in the organization and function of brain synapses (connection between brain cells)—were also evident. Interestingly, the biochemical changes were reversed after the administration of the antihypertensive drug “losartan.” A similar reversal was observed after knocking out the EP1 gene.
Overall, these findings suggest that angiotensin II-AT1 and prostaglandin E2-EP1 systems could be novel therapeutic targets for hypertension-induced dementia.
Prof. Mouri concludes by saying, “This study is of particular social and economic importance because the annual social cost of dementia treatment in Japan is surging like never before”. Therefore, developing preventive and therapeutic drugs for dementia seems critical for Japan’s rapidly aging population.”
About Fujita Health University
Fujita Health University is a private university situated in Toyoake, Aichi, Japan. It was founded in 1964 and houses one of the largest teaching university hospitals in Japan in terms of the number of beds. With over 900 faculty members, the university is committed to providing various academic opportunities to students internationally. Fujita Health University has been ranked eighth among all universities and second among all private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. THE University Impact Rankings 2019 visualized university initiatives for sustainable development goals (SDGs). For the “good health and well-being” SDG, Fujita Health University was ranked second among all universities and number one among private universities in Japan. The university became the first Japanese university to host the "THE Asia Universities Summit" in June 2021. The university’s founding philosophy is “Our creativity for the people (DOKUSOU-ICHIRI),” which reflects the belief that, as with the university’s alumni and alumnae, current students also unlock their future by leveraging their creativity.
About Professor Akihiro Mouri from Fujita Health University
Dr. Akihiro Mouri serves as a Professor at Fujita Health University’s School of Health Sciences. He has over 100 well-cited publications and multiple patents to his credit. Prof. Mouri’s research group primarily focuses on epidemiological and genetic findings in humans and creates animal models of psychiatric and neurological disorders to explore various pathological and pathogenic mechanisms. The group conducts behavioral and neurochemical experiments to develop new therapeutic agents, phytochemicals, and diagnostic biomarkers. Prof. Mouri has won several distinguished awards for his outstanding research contributions.
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17H04252, 20K07931, and 20K16679) and by the Japan Science and Technology Agency (JST) FOREST Program (JPMJFR215H). In addition, this work was supported by a grant from the Education and Research Facility of Animal Models for Human Diseases at Fujita Health University, a research grant from the Smoking Research Foundation, and the Takeda Science Foundation.
British Journal of Pharmacology
Method of Research
Subject of Research
High salt induces cognitive impairment via the interaction of angiotensin II-AT1 and prostaglandin E2-EP1 systems
Article Publication Date
The authors declare no potential conflicts of interest