A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

Alzheimer's disease (AD), the most prevalent, age-related, neurodegenerative disease, is associated with the accumulation of amyloid beta (Aβ) and oxidative stress. However, the sporadic nature of late-onset AD has suggested that other factors, such as aluminium may be involved. Aluminium (Al³⁺) is the most ubiquitous neurotoxic metal on earth, extensively bioavailable to humans. Despite this, the link between Al³⁺ and AD has been debated for decades and remains controversial. Using Saccharomyces cerevisiae as a model organism expressing Aβ42, this study aimed to examine the mechanisms of Al³⁺ toxicity and its interactions with Aβ42. S. cerevisiae cells producing Aβ42 treated with varying concentrations of Al³⁺ were examined for cell viability, growth inhibition, and production of reactive oxygen species (ROS). Al³⁺ caused a significant reduction in cell viability: cell death in yeast producing green fluorescent protein tagged with Aβ42 (GFP-Aβ42) was significantly higher than in cells producing green fluorescent protein (GFP) alone. Additionally, Al³⁺ greatly inhibited the fermentative growth of yeast producing GFP-Aβ42, which was enhanced by ferric iron (Fe³⁺), while there was negligible growth inhibition of GFP cells. Al³⁺- induced ROS levels in yeast expressing native Aβ42 were significantly higher than in empty vector controls. These findings demonstrate Al³⁺ has a direct, detrimental toxic synergy with Aβ42 that can be influenced by Fe³⁺, causing increased oxidative stress. Thus, Al³⁺ should be considered as an important factor, alongside the known characteristic hallmarks of AD, in the development and aetiology of the disease.