Using a transgenic mouse model of Alzheimer’s disease, scientists demonstrate a definitive connection with oxidative brain damage.
The progression of Alzheimer disease (AD) is closely associated with oxidative brain damage, results of a study published in Biomedicines show.
Previously, the same investigators found that oxidation levels were substantially higher in older rats with vitamin E deficiency than younger rats. Additionally, the reactive oxygen species (ROS) production via mitochondrial oxidation could damage brain cells, implying a strong link between AD and mitochondrial dysfunction.
The mitochondrial electron transport chain, which is required for generating energy during cellular processes, also produces ROS that attack tissues and cause oxidative damage. The damage can lead to mitochondrial dysfunction and even cell death.
Because the brain uses more oxygen than other organs, it is the most vulnerable to ROS damage.
According to other literature, ROS also causes the buildup of amyloid-β (Aβ), which marks the onset of AD.
The investigators used 3 groups of mice with AD, aged 3, 6, and 20 months, along with healthy controls. For testing their cognitive and coordination abilities, the mice were examined in 2 experiments: the Morris water maze and the Rota-rod test.
Investigators noticed that the mice with AD took longer to complete their maze goals but did not slow down. In the Rota-rod test, the 6- and 20-month-old mice with AD 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 2 groups, as the control mice were heavier than the AD mice,” Koji Fukui, a professor at the Shibaura Institute of Technology, said in a statement.
Therefore, these results suggested that the mice with AD were cognitively impaired but did not have any coordination issues.
To identify which AD-related proteins were responsible for such cognitive impairment, the investigators collected tissue samples from various parts of the brain from both groups of mice and assessed the levels of oxidative markers in the sample.
First, they found that mice with AD had higher levels of Aβ, with a gradual increase observed with age. Additionally, 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 alteration in the levels of the tau protein, which is another marker that accumulates in AD pathology.
Overall, investigators confirmed that Aβ1-42 aggregation in the hippocampus caused cognitive impairment in mice with AD.
Additionally, the investigators speculated about ROS-induced mitochondrial damage being closely related to neuron survival. To evaluate this hypothesis, they determined the levels of some key mitochondrial oxidative enzymes, including nicotinamide-nucleotide adenylyltransferase (NMNAT)-3, which exhibits anti-aging effects.
Although NMNAT-3 was found to be lowered, levels of 3-nitrotyrosine, an indicated of higher oxidation, increased with age.
These results show that oxidation causes mitochondrial dysfunction and leads to cognitive dysfunction, Fukui said.
Investigators are optimistic about the potential implication of these results, particularly in increasing the intake of antioxidant compounds that can help our bodies mitigate ROS.
"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,” Fukui said.
Study reveals likely link between mitochondrial dysfunction and age-dependent cognitive disorders. EurekAlert. News release. February 14, 2022. Accessed February 14, 2022. https://www.eurekalert.org/news-releases/943122