P4‐185: Mitochondrial dysfunction in Alzheimer's disease

There is accumulating evidence suggesting that oxidative stress occurs prior to the onset of symptoms in Alzheimer disease (AD) and such oxidative changes are pervasive throughout the body being detected peripherally as well as associated with the vulnerable regions of the brain affected in disease. The complex nature and genesis of oxidative damage in AD can now be partly answered by mitochondrial abnormalities that can initiate oxidative stress. The alteration of mitochondrial function leads not only to a decrease in energy levels but also to an increase in reactive oxygen species (ROS) production. Besides being a main intracellular site of ROS production, mitochondria are also targets for oxidative damage, which amplify oxidative stress. We aimed to evaluate the role and fate of mitochondria in AD. We evaluated the respiratory chain, oxidative phosphorylation system, hydrogen peroxide production and the capacity of mitochondria to accumulate calcium. We also compared oxidative and apoptotic markers in fibroblasts obtained from AD subjects at basal conditions and after pre-treatment with lipoic acid and N-acetyl cysteine. Finally, we performed light and electron microscopic analyses and immunoblot assays on human brain tissue. Isolated brain mitochondria exposed to amyloid β peptide (Aβ) present an impaired respiratory chain and oxidative phosphorylation system, a decreased capacity to accumulate Ca2+ and produce higher levels of hydrogen peroxide. Moreover, mitochondrial dysfunction induced by Aβ is highly exacerbated by aging. These results are supported by studies done with fibroblasts obtained from AD patients that show a positive correlation between the levels of oxidative stress markers and mitochondrial dysfunction. In addition, the antioxidants lipoic acid and N-acetyl cysteine show a significant protective effect. Studies performed with human brain tissue co-substantiate the existence of prominent mitochondrial abnormalities in AD. By using two mitochondrial markers, lipoic acid and cytochrome oxidase, we observed that mitochondria from AD cases are under an increased autophagic degradation. Together these results support the idea that mitochondria are preferential targets in AD. Furthermore, given the importance of mitochondria as a primary source of oxidative stress in aging and age-related diseases the use of antioxidants could be therapeutically useful.