The mitochondrial electron transport chain, which is required for generating energy during cellular processes, also produces reactive oxygen species (ROS) that attack tissue and cause oxidative damage. This damage can cause mitochondrial dysfunction and even lead to cell death. Since our brain uses more oxygen than other organs, it is more vulnerable to this ROS damage.
According to literature, ROS also causes the buildup of amyloid-β (Aβ), which marks the onset of Alzheimer's disease (AD), a serious irreversible neurodegenerative disorder. Treatments for AD do not stop its progression, necessitating the development of new therapeutics.
In a prior study, a team of scientists found that oxidation levels were substantially higher in older rats with vitamin E deficiency than in younger rats. Furthermore, ROS production via mitochondrial oxidation could damage brain cells, implying a strong link between AD and mitochondrial dysfunction. To improve this understanding, the same group of scientists has now demonstrated that the progression of AD is closely associated with oxidative brain damage. The study, led by Prof. Koji Fukui, along with his colleagues Mr Naoki Yoshida, Mr. Yugo Kato, and Prof. Hirokatsu Takatsu, was recently published in Biomedicines. “We showed that oxidation negatively impacted the mitochondria which led to cognitive dysfunction,” explains Prof. Fukui, who is the corresponding author of the study.
The scientists used three groups of AD mice aged 3, 6, and 20 months, along with healthy controls. For testing their cognitive and coordination abilities, the mice were examined in two well-known experiments: the Morris water maze and the Rota-rod test. They discovered that the AD mice took longer to complete their maze goals but did not slow down. In the Rota-rod test, the 6- and 20-month-old AD mice stayed on the rod for a longer time, while the age-matched control mice fell quicker. Prof. Fukui explains, “The difference in fall time could be attributed to the weight difference between the two groups, as the control mice were heavier than the AD mice.” These results suggested that AD mice were cognitively impaired but did not have any coordination issues.
To identify which AD-related proteins were responsible for such cognitive impairment, the authors collected tissue samples from various parts of the brain from both groups of mice and assessed the levels of oxidative markers in the samples. First, they found that AD mice had higher levels of Aβ, with a gradual increase observed with age. To their surprise, the AD-related protein Aβ1-42 was significantly higher in the hippocampus than in other parts of the brain. However, they did not find any alterations in the levels of the tau protein, which is another marker that accumulates in AD pathology. Overall, it was confirmed that Aβ1-42 aggregation in the hippocampus caused cognitive impairment in AD mice.
The team also had speculations about ROS-induced mitochondrial damage being closely related to neuron survival. To validate their hypothesis, they determined the levels of some key mitochondrial oxidative enzymes, including nicotinamide-nucleotide adenylyltransferase (NMNAT)-3, which exhibits anti-ageing effects. While NMNAT-3 was found to be lowered, levels of 3-NT (3-nitrotyrosine), an indicator of higher oxidation, increased with age in AD mice. “With reduced levels of NMNAT-3 and higher levels of 3-NT, it is evident that oxidation causes mitochondrial dysfunction, and eventually leads to cognitive dysfunction,” comments Prof. Fukui.
The team is optimistic about the potential implications of their results, particularly in increasing the intake of antioxidant compounds that can help our bodies mitigate ROS. In fact, many natural antioxidants, such as vitamins E and C, can be obtained from dietary sources. Prof. Fukui concludes by surmising, "If mitochondria can be protected from ROS, mitochondrial function and cognitive function may be maintained. Future research should concentrate on developing diagnostic markers to detect early alterations in the brain, as well as exploring compounds with high antioxidant activity in mitochondria."
About Shibaura Institute of Technology (SIT), Japan
Shibaura Institute of Technology (SIT) is a private university with campuses in Tokyo and Saitama. Since the establishment of its predecessor, Tokyo Higher School of Industry and Commerce, in 1927, it has maintained “learning through practice” as its philosophy in the education of engineers. SIT was the only private science and engineering university selected for the Top Global University Project sponsored by the Ministry of Education, Culture, Sports, Science and Technology and will receive support from the ministry for 10 years starting from the 2014 academic year. Its motto, “Nurturing engineers who learn from society and contribute to society,” reflects its mission of fostering scientists and engineers who can contribute to the sustainable growth of the world by exposing their over 8,000 students to culturally diverse environments, where they learn to cope, collaborate, and relate with fellow students from around the world.
About Professor Koji Fukui from SIT, Japan
Prof. Koji Fukui serves as a Professor at the Graduate School of Engineering and Science at Shibaura Institute of Technology (SIT) in Japan. In 2003, he received his Ph.D. in Engineering from SIT. He studied abroad at the National Institute on Aging for a year from 2014 (P.I. Prof. de Cabo Rafael). His research focuses on oxidative stress and ageing, with a particular emphasis on Vitamin E as a therapeutic substance for neurodegenerative disorders. His goal is to figure out how the brain ages and develops neuro-diseases. Prof. Fukui is a Councilor of the Japan Oxidative Stress Society and an active member of the Japan Society for Bioscience and Biotechnology. He is also a director in the Japan Society for Biomedical Gerontology. He is actively involved in joint research with laboratories all around the world and has published several research articles. In February 2021, Prof. Fukui received the Japan Vitamin Society Topics Contribution Award. He was also awarded the prestigious Japan Oxidative Stress Society Academic Award in August 2020.
The author(s) received no specific funding for this work.
Method of Research
Subject of Research
Relationship between cognitive dysfunction and age-related variability in oxidative markers in isolated mitochondria of Alzheimer’s disease transgenic
Article Publication Date
The authors declare no competing interests