Oxidation in a respiratory brainstem area of an Alzheimer's rat model

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting more than 50 million individuals worldwide. Sporadic AD comprises 95% of all cases and is most commonly known for its hallmark symptoms of cognitive decline and memory degradation. In addition, respiratory dysfunction is found in up to 80% of AD patients and often manifests as sleep-disordered breathing. In the early stages of AD, increased reactive oxygen species cause widespread oxidative stress, which can damage cellular components and severely impact neuronal activity. While the respiratory dysfunction and oxidative stress is well known, there is little known about the underlying mechanisms and their potential intersection in AD patients. This study used the Streptozotocin (STZ)-AD rat model, which is the only well-established model mimicking sporadic AD with its multifactorial presentations including AD hallmark symptoms and respiratory dysfunction. Two weeks after induction of the STZ-AD rat model (2 mg/kg STZ), we analyzed targets of oxidative stress in a critical respiratory control area in the brainstem, the nucleus Tractus Solitarii (nTS). Immunohistochemistry was used to fluorescently stain brainstem sections in order to analyze for oxidation of lipids (4-hydroxynonenal, 4-HNE), DNA (8-hydroxyguanine, 8-OHG), and protein sulfhydryl groups (dimedone-tagged sulfenic acid). While there was no pronounced lipid peroxidation, the STZ-AD group had significantly increased levels of DNA oxidation when compared to the control (CTL). In addition, sulfhydryl groups, which are present on many cellular proteins, also had a significantly increased baseline oxidation in the STZ-AD group when compared to CTL. Oxidation of these sulfhydryl groups is known to be responsible for altering ion channel function and thus neuronal activity. Reducing agent Dithiothreitol (DTT) was able to revert sulfhydryl oxidation in STZ-AD to its reduced form, while CTL rats did not change from baseline. On the other hand, addition of the oxidizing agent hydrogen peroxide increased sulfhydryl oxidation in CTL, but not in STZ-AD. Overall, our results show that STZ-AD causes increased oxidation throughout a key brainstem area of respiration. This oxidation also affects protein components important for neuronal activity, which could be an underlying cause for the respiratory dysfunction in AD. Funding sources include the Kirksville College of Osteopathic Medicine Biomedical Sciences Graduate Program and the National Institutes of Health (R15AG065927). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.