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How Oxidation Can Lead to Mitochondrial Dysfunction and Age-Dependent Cognitive Disorders
The intake of antioxidants like Vitamins C and E may help our bodies to mitigate the production of reactive oxygen species and help to maintain mitochondrial and cognitive function.

Playing host to one of the most important processes in the human body, the mitochondria are responsible for generating energy by “taking in” oxygen and glucose. However, the mitochondrial electron transport chain, which is essential for producing ATP, the energy currency of the cell, can also produce reactive oxygen species (ROS) which in turn can cause oxidative damage, disrupt mitochondrial function, and lead to cell death. Because the brain consumes more oxygen than any other organ, it is especially vulnerable to ROS damage. In fact, many neurodegenerative disorders such as Alzheimer’s disease are strongly linked to the accumulation of oxidative damage. In recent years, studies have found that ROS can also promote the build-up of amyloid-β (Aβ), a famous and well-studied hallmark of Alzheimer’s disease. However, scientists have yet to establish a definitive link between mitochondrial oxidative damage and brain function decline.

Seeking to clarify the relationship between mitochondrial dysfunction and the onset and progression of Alzheimer’s disease, Professor Koji Fukui at Shibaura Institute of Technology and his colleagues Naoki Yoshida, Yugo Kato, and Professor Hirokatsu Takatsu embarked on an investigation that led them to demonstrate how the progression of Alzheimer’s Disease is closely associated with oxidative damage.

“We showed that oxidation negatively impacted the mitochondria which led to cognitive dysfunction,” explains Prof. Fukui, who is the corresponding author of the study.

Previously, Prof. Fukui and his team discovered that oxidation levels were significantly higher in older rats with vitamin E deficiency than in younger rats. Additionally, the production of ROS via mitochondrial oxidation was found to damage brain cells, suggesting a strong link between Alzheimer’s disease and mitochondrial dysfunction.

In their current study, the researchers used three groups of transgenic mice aged 3, 6, and 20 months as an Alzheimer’s disease model, along with healthy controls and assessed their cognitive and coordination abilities. Using the Morris water maze and Rota-rod test, the researchers found that while the Alzheimer’s disease mice took a longer time to complete their maze goals, they did not slow down. In the Rota-rod test, the 6- and 20-month-old mice stayed on the rod for a longer time, while the age-matched control mice fell quicker.

“The difference in fall time could be attributed to the weight difference between the two groups, as the control mice were heavier than the [Alzheimer’s disease] mice,” explained Prof. Fukui. Furthermore, these results suggested that although the Alzheimer’s disease mice were cognitively impaired, their coordination skills were not compromised.

To determine which proteins were responsible for their cognitive dysfunction, the researchers gathered tissue samples from various parts of the brain from both groups of mice and examined the levels of oxidative markers in the samples. Their results revealed that the Alzheimer’s disease mice exhibited higher levels of Aβ, with a gradual increase with age. Interestingly, the scientists also found that the Alzheimer’s disease-related protein Aβ1-42 was substantially higher in the hippocampus than in other parts of the brain. Since the scientists did not detect any changes in the levels of tau protein, which is another marker that builds up in Alzheimer’s disease pathology, they confirmed that the aggravation of Aβ1-42 in the hippocampus led to cognitive impairment in the Alzheimer’s disease mice.

In addition to these findings, the team also speculated that ROS-induced mitochondrial damage is closely linked to neuronal survival. To validate their hypothesis, the scientists assessed the levels of some key mitochondrial oxidative enzymes, including nicotinamide-nucleotide adenylyltransferase (NMNAT)-3, which exhibits anti-ageing effects. It was found that NMNAT-3 levels decreased, whereas levels of 3-NT (3-nitrotyrosine), an indicator of higher oxidation, increased with age in Alzheimer’s disease 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,” commented Prof. Fukui.

Given these results, the scientists are excited about the potential implications of their findings. For one, increasing the intake of antioxidant compounds, such as vitamins E and C, can help prevent the production of ROS and potentially mitigate cognitive dysfunction.

“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,” said Prof. Fukui.

Source: Yoshida et al. (2022). Relationship between Cognitive Dysfunction and Age-Related Variability in Oxidative Markers in Isolated Mitochondria of Alzheimer’s Disease Transgenic Mouse Brains, Biomedicines, 10(2), 281.

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