Tyramine and Amyloid Beta 42: A Toxic Synergy

Implicated in various diseases including Parkinson's disease, Huntington's disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be no studies investigating a connection of tyramine to Alzheimer's disease. This study aimed to examine whether tyramine could be involved in AD pathology by usingSaccharomyces cerevisiaeexpressing A beta 42. S. cerevisiaecells producing native A beta 42 were treated with different concentrations of tyramine, and the production of reactive oxygen species (ROS) was evaluated using flow cytometric cell analysis. There was dose-dependent ROS generation in wild-type yeast cells with tyramine. In yeast producing A beta 42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of A beta 42 and tyramine. The addition of exogenous reduced glutathione (GSH) was found to rescue the cells with increased ROS, indicating depletion of intracellular GSH due to tyramine and A beta 42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-A beta 42, while there was no growth inhibition when cells were producing GFP. Tyramine was also demonstrated to cause increased mitochondrial DNA damage, resulting in the formation of petite mutants that lack respiratory function. These findings indicate that there can be a detrimental synergy between A beta 42 and tyramine, which could be considered in Alzheimer's disease. This work also demonstrates the utility of yeast as a model for studying toxic agents such as A beta 42, tyramine, and agents that might exacerbate AD pathology.