Tyramine and Amyloid Beta 42: A Toxic Synergy

Abstract

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 using Saccharomyces cerevisiae expressing Aβ42. S. cerevisiae cells producing native Aβ42 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 Aβ42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of Aβ42 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 Aβ42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-Aβ42, 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 Aβ42 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 Aβ42, tyramine, and agents that might exacerbate AD pathology.

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

“…S. cerevisiae yeast strain BY4743 ( MATa/α his3Δ1/his3Δ1 LYS2/lys2Δ0 met15Δ0/MET15 ura3Δ0/ura3Δ0 leu2Δ0/leu2Δ0 ) was the host strain used in this study. The plasmids p416GPD.GFPAβ, p416GPD.GFP, pYEX.Aβ, and pYEX.BX were transformed into the host strain as previously described in [ 17 , 19 ]. Briefly, isolated colonies of S. cerevisiae BY4743 with a diameter of 3–4 mm were grown on YEPD and transformed using an EZ transformation kit.…”

“…Saccharomyces cerevisiae has proven to be a facile model for studying AD, providing unprecedented insights into the underlying molecular basis of ageing and in deciphering the complexity of disease pathology involved in AD [ 13 , 15 , 16 ]. We have developed yeast-based models for investigating the effects of compounds that alleviate the toxicity associated with Aβ 42 and those that synergistically increase Aβ toxicity [ 17 , 18 , 19 ]. For example, the model system discussed above has been used to demonstrate a toxic synergy between tyramine and Aβ42 via oxidative stress and mitochondrial dysfunction [ 19 ].…”

“…We have developed yeast-based models for investigating the effects of compounds that alleviate the toxicity associated with Aβ 42 and those that synergistically increase Aβ toxicity [ 17 , 18 , 19 ]. For example, the model system discussed above has been used to demonstrate a toxic synergy between tyramine and Aβ42 via oxidative stress and mitochondrial dysfunction [ 19 ]. In this study, the yeast-based model system has been used to investigate cellular responses to Aβ42 and Al 3+ by treating S. cerevisiae expressing GFP–Aβ42 and GFP alone with varying concentrations of Al 3+ .…”

“…In this study, the yeast-based model system has been used to investigate cellular responses to Aβ42 and Al 3+ by treating S. cerevisiae expressing GFP–Aβ42 and GFP alone with varying concentrations of Al 3+ . The comparison between these two constructs can be made due to the growth of transformants under normal conditions being highly similar and robust [ 19 ]. Using a growth inhibition assay and viability measurements coupled with ROS analysis, this report demonstrates that the neurotoxic properties of Al 3+ and Aβ42 are exacerbated by one another, causing an adverse synergistic effect on growth via increased oxidative damage.…”

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

“…The outcomes observed in yeast after heterologous expression of such human proteins has served as the basis for further studies and unravelling of the molecular pathogenesis caused by these proteins. These yeast models have provided unique frontier for screening of both cytoprotective and cytotoxic compounds [18,21,[397][398][399]. Several yeast reporter systems have also been developed, which aid AD research and provide directions for future research [400,401].…”