Yeast contributions to Alzheimer’s Disease

McDonald, Jamieson B; Dhakal, Sudip; Macreadie, Ian

doi:10.29245/2690-0009/2020/2.1114

Cited by 9 publications

(9 citation statements)

References 76 publications

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

McDonald

Dhakal

Macreadie

2021

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

McDonald

Dhakal

Macreadie

2021

IJMS

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“…This phenomenon aligns well with human ageing and advocates that the yeast ageing can be an excellent tool to understand eukaryotic ageing [10]. Further elaboration on how yeast provides an excellent platform for studying AD is reviewed elsewhere [11][12][13]. In another study, differential gene expression analysis between GFP-Aβ 42 producing yeast compared with GFP producing yeast showed high expression of AHP1 in GFP-Aβ 42 producing cells [14].…”

Section: Introductionmentioning

confidence: 81%

Trans-Chalcone Plus Baicalein Synergistically Reduce Intracellular Amyloid Beta (Aβ42) and Protect from Aβ42 Induced Oxidative Damage in Yeast Models of Alzheimer’s Disease

Dhakal

Ramsland

Adhikari

et al. 2021

IJMS

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Finding an effective therapeutic to prevent or cure AD has been difficult due to the complexity of the brain and limited experimental models. This study utilized unmodified and genetically modified Saccharomyces cerevisiae as model organisms to find potential natural bioactive compounds capable of reducing intracellular amyloid beta 42 (Aβ42) and associated oxidative damage. Eleven natural bioactive compounds including mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans-chalcone were screened for their ability to reduce intracellular green fluorescent protein tagged Aβ42 (GFP-Aβ42) levels. The two most effective compounds from the screens were combined in varying concentrations of each to study the combined capacity to reduce GFP-Aβ42. The most effective combinations were examined for their effect on growth rate, turnover of native Aβ42 and reactive oxygen species (ROS). The bioactive compounds except mangiferin and urolithin A significantly reduced intracellular GFP-Aβ42 levels. Baicalein and trans-chalcone were the most effective compounds among those that were screened. The combination of baicalein and trans-chalcone synergistically reduced GFP-Aβ42 levels. A combination of 15 μM trans-chalcone and 8 μM baicalein was found to be the most synergistic combination. The combination of the two compounds significantly reduced ROS and Aβ42 levels in yeast cells expressing native Aβ42 without affecting growth of the cells. These findings suggest that the combination of baicalein and trans-chalcone could be a promising multifactorial therapeutic strategy to cure or prevent AD. However, further studies are recommended to look for similar cytoprotective activity in humans and to find an optimal dosage.

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“…The most important one stems from the conservation of the molecular mechanisms in yeast that inform about fundamental processes of human biology 7 . Energy metabolism, genetics, vesicle trafficking, cell division, protein homeostasis networks, lipid metabolism, stress response pathways and cell death pathways are some major processes that are conserved between humans and yeasts 8 . The different phases of yeast growth also allow us to understand chronological and replicative lifespans 9 .…”

Section: Yeast Models and Bioassays To Study Admentioning

confidence: 99%

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

Dhakal¹

2021

Microbiol. Aust.

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The difficulties in performing experimental studies related to diseases of the human brain have fostered a range of disease models from highly expensive and complex animal models to simple, robust, unicellular yeast models. Yeast models have been used in numerous studies to understand Alzheimer's disease (AD) pathogenesis and to search for drugs targeting AD. Thanks to the conservation of fundamental eukaryotic processes including ageing and the availability of appropriate technological platforms, budding yeast are a simple model eukaryote to assist with understanding human cell biology, offering a platform to study human diseases. This article aims to provide insights from yeast models on the contributions of amyloid beta, a causative agent in AD, and recent research findings on AD chemoprevention.

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Yeast contributions to Alzheimer’s Disease

Cited by 9 publications

References 76 publications

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

Trans-Chalcone Plus Baicalein Synergistically Reduce Intracellular Amyloid Beta (Aβ42) and Protect from Aβ42 Induced Oxidative Damage in Yeast Models of Alzheimer’s Disease

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

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