A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

Abstract

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.

‘The awesome power of yeast’ in Alzheimer’s disease research

“…The potential role of these novel modifiers of Ab toxicity, that are present in human body, can be identified using the yeast models. This opens up avenues for new dimensions in AD research 25,26 . These studies are important because the sporadic nature of AD suggests factors in addition to Ab may be involved in AD.…”

“…Engineered yeast have also been used to identify compounds that exhibit toxic synergies with Ab. In separate recent studies, both tyramine and aluminium exacerbated Ab toxicity by enhancing the ROS inside cells 25,26 . Aluminium is the most abundant neurotoxic metal present in our surroundings including our food and consumer products.…”

“…On the contrary, the ability of yeasts to grow without functional mitochondria allows discovery of chemicals or biomolecules that directly affect mitochondria, its turnover and biogenesis 9 . For example, the respiratory growth (growth supported by mitochondria) of the yeast cells was inhibited more in GFP-Ab transformant yeast cells compared to those in GFP transformants in the presence of tyramine and aluminium indicating increased mitochondrial and mitophagy defects in these cells 25,26 . These studies illustrated that yeast provided a unique platform to investigate compounds that affect mitochondrial health, which is impossible in higher eukaryotes.…”

“…Aluminium is the most abundant neurotoxic metal present in our surroundings including our food and consumer products. Although the toxic effect of aluminium in AD has been proposed for decades with limited evidence, the recent yeast study illustrated its ability to enhance Ab toxicity suggesting its potential role in AD 25 . Similarly, tyramine and Ab's synergistic toxicity indicates tyramine's potential role in AD 26 .…”

Identification of Crocin as a New hIAPP Amyloid Inhibitor via a Simple Yet Highly Biospecific Screening System

“…Yeast, especially S. cerevisiae , has been successfully used as an effective tool to model protein aggregation in human disorders, including Alzheimer (AD), Parkinson (PD), Huntington (HD) and prion diseases [9–13] . Usually, the protein aggregation in S. cerevisiae was recapitulated by measuring the fluorescence intensity of fluorescent protein tagged to the amyloid protein [14,15] . The limitation of this method is that the fluctuation of fluorescence needs higher expression of the target protein, which was toxic to the cells [14] .…”