Interplay of Energetics and ER Stress Exacerbates Alzheimer's Amyloid-beta (A beta) Toxicity in Yeast
Artikel i vetenskaplig tidskrift, 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.

energetics

yeast

Alzheimer's disease

amyloid-beta

ER stress

Författare

Xin Chen

Chalmers, Biologi och bioteknik, Systembiologi

Mark Bisschops

Chalmers, Biologi och bioteknik, Systembiologi

Nisha Rani Agarwal

Chalmers, Biologi och bioteknik, Kemisk biologi

Boyang Ji

Chalmers, Biologi och bioteknik, Systembiologi

K. P. Shanmugavel

Chalmers University of Technology

Dina Petranovic Nielsen

Chalmers, Biologi och bioteknik, Systembiologi

Frontiers in Molecular Neuroscience

1662-5099 (ISSN)

Vol. 10 232

Ämneskategorier

Cellbiologi

DOI

10.3389/fnmol.2017.00232