Linking Mitochondrial Dysfunction and Age-Related Cognitive Decline
Age-related mitochondrial dysfunction is particularly relevant to the progression of neurodegenerative conditions, as the brain is an energy-hungry organ. Mitochondria provide the chemical energy store molecules needed to power cellular operations, but their function declines with age throughout the body. Cells change their behavior for the worse as a consequence. Some part of this involves characteristic age-related changes in the expression of proteins necessary for mitochondrial function, another part is damage to mitochondrial DNA, such as via oxidative reactions that become more common in aged tissues, leading to loss of production of necessary proteins and detrimental alterations to mitochondrial behavior. Approaches, such as mitochondrial transplantation, that might at least temporarily restore mitochondrial function in old people should be a high priority for the longevity industry.
Many neurodegenerative disorders, including Alzheimer's disease (AD), are strongly associated with the accumulation of oxidative damage. Transgenic animal models are commonly used to elucidate the pathogenic mechanism of AD. Beta amyloid (Aβ) and tau hyperphosphorylation are very famous hallmarks of AD and well-studied, but the relationship between mitochondrial dysfunction and the onset and progression of AD requires further elucidation.
In this study we used transgenic mice (the strain name is 5xFAD) at three different ages (3, 6, and 20 months old) as an AD model. Cognitive impairment in AD mice occurred in an age-dependent manner. Aβ1-40 expression significantly increased in an age-dependent manner in all brain regions with or without AD, and Aβ1-42 expression in the hippocampus increased at a young age. In a Western blot analysis using isolated mitochondria from three brain regions (cerebral cortex, cerebellum, and hippocampus), NMNAT-3 expression in the hippocampi of aged AD mice was significantly lower than that of young AD mice. SOD-2 expression in the hippocampi of AD mice was lower than for the age-matched controls. However, 3-NT expression in the hippocampi of AD mice was higher than for the age-matched controls. NQO-1 expression in the cerebral cortex of AD mice was higher than for the age-matched controls at every age that we examined. However, hippocampal NQO-1 expression in 6-month-old AD mice was significantly lower than in 3-month-old AD mice.
These results indicate that oxidative stress in the hippocampi of AD mice is high compared to other brain regions and may induce mitochondrial dysfunction via oxidative damage. Protection of mitochondria from oxidative damage may be important to maintain cognitive function.