Interplay of Energetics and ER Stress Exacerbates Alzheimer's Amyloid-beta (A beta) Toxicity in Yeast
Journal article, 2017

Alzheimer's disease (AD) is a progressive neurodegeneration. Oligomers of amyloid-beta peptides (A beta) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of A beta associated with AD are A beta 40 and A beta 42, 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 A beta 40 or A beta 42 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 A beta 42 expression, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondria' functionality and ATP generation in A beta 42 expressing cells, which matched with observed aberrant mitochondria' structures. Genome-wide expression level analysis showed that A beta 42 expression triggered strong ER stress and unfolded protein responses. Equivalent expression of A beta 40, 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 A beta toxicity signals into particular cell fate programs, and further enhance their potential as a discovery platform to identify possible therapies.

Alzheimer's disease

amyloid-beta

energetics

ER stress

yeast

Author

Xin Chen

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Mark Bisschops

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Nisha Rani Agarwal

Chalmers, Biology and Biological Engineering, Chemical Biology

Boyang Ji

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Kumaravel Ponnandai Shanmugavel

Chalmers, Biology and Biological Engineering, Chemical Biology

Dina Petranovic Nielsen

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Frontiers in Molecular Neuroscience

1662-5099 (ISSN)

Vol. 10 232

Subject Categories

Cell Biology

DOI

10.3389/fnmol.2017.00232

More information

Latest update

7/23/2018