Interplay of Energetics and ER Stress Exacerbates Alzheimer's Amyloid-ß (Aß) Toxicity in Yeast.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegeneration. Oligomers of amyloid-ß peptides (Aß) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of Aß associated with AD are Aß40 and Aß42, the latter being more toxic and prone to form oligomers. Here, we took a systems biology approach to study two humanized yeast AD models which expressed either Aß40 or Aß42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected chronological lifespan and reduced variations during cell growth. Reduced growth rates and biomass yields were observed upon Aß42 expression, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in Aß42 expressing cells, which matched with observed aberrant mitochondrial structures. Genome-wide expression level analysis showed that Aß42 expression triggered strong ER stress and unfolded protein responses. Equivalent expression of Aß40, however, induced only mild ER stress, which resulted in hardly affected physiology. Using AD yeast models in well-controlled cultures strengthened our understanding on how cells translate different Aß toxicity signals into particular cell fate programs, and further enhance their potential as a discovery platform to identify possible therapies.