Study reveals likely link between mitochondrial dysfunction and age-
dependent cognitive disorders

Date:
February 14, 2022
Source:
Shibaura Institute of Technology
Summary:
Increased oxidative damage is linked to neurodegenerative disorders
such as Alzheimer's disease (AD). Even though the pathophysiology
of AD has been widely investigated, the likely relationship between
mitochondrial dysfunction and the disease remains largely unknown. A
research team has now confirmed that AD progression is linked to
oxidative brain damage, which impairs cognitive function in AD
transgenic mice in an age- dependent manner.



FULL STORY ========================================================================== Increased oxidative damage is linked to neurodegenerative disorders such
as Alzheimer's disease (AD). Even though the pathophysiology of AD has
been widely investigated, the likely relationship between mitochondrial dysfunction and the disease remains largely unknown. A research team
led by Prof. Koji Fukui from Japan's Shibaura Institute of Technology
has confirmed that AD progression is linked to oxidative brain damage,
which impairs cognitive function in AD transgenic mice in an age-dependent manner.


==========================================================================
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-b (Ab),
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 Ab, with a gradual increase observed with age. To their surprise, the AD-related protein Ab1-42 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 Ab1-42 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."
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========================================================================== Journal Reference:
1. Naoki Yoshida, Yugo Kato, Hirokatsu Takatsu, Koji
Fukui. Relationship
between Cognitive Dysfunction and Age-Related Variability in
Oxidative Markers in Isolated Mitochondria of Alzheimer's Disease
Transgenic Mouse Brains. Biomedicines, 2022; 10 (2): 281 DOI:
10.3390/biomedicines10020281 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214095824.htm

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