Abstract
Alzheimer's disease (AD) is a progressive neurodegeneration. Oligomers of amyloid-β peptides (Aβ) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of Aβ associated with AD are Aβ40 and Aβ42, 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 Aβ40 or Aβ42 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 Aβ42 expression, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in Aβ42 expressing cells, which matched with observed aberrant mitochondrial structures. Genome-wide expression level analysis showed that Aβ42 expression triggered strong ER stress and unfolded protein responses. Equivalent expression of Aβ40, 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 Aβ toxicity signals into particular cell fate programs, and further enhance their potential as a discovery platform to identify possible therapies.
Highlights
Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder, and its incidence is projected to rise due to the increasing life expectancy (Wyss-Coray, 2016)
By controlling the culture parameters, we reduced the number of irrelevant and sidetracking variables and produced a considerable amount of genome-wide and physiological information concerning the energetic consequences of amyloid-β peptides (Aβ) expression, as well as revealing how these different Aβ toxic isoforms interfered with cellular metabolism and stress response pathways, causing pronounced physiological effects
Overall these results suggest an altered redox-cofactor balancing in the heterologous Aβ42 expressing strain (Bakker et al, 2001)
Summary
Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder, and its incidence is projected to rise due to the increasing life expectancy (Wyss-Coray, 2016). Due to incomplete knowledge on the underlying mechanisms that lead to cellular dysfunction in AD, it is difficult to design effective therapies. Accumulation of amyloid-β (Aβ) plaques in the brain is a key neuropathological feature of AD (Hardy and Selkoe, 2002). Aβ peptides (ranging in length from 39 to 43 amino acids) are generated by amyloidogenic processing of the transmembrane amyloid precursor protein (APP; Selkoe, 2001). Differential cleavage of APP produces two major Aβ peptide isoforms, Aβ40 and Aβ42, of which Aβ40 is most abundantly produced, but Aβ42 is the predominant isoform found in AD plaques (Younkin, 1998).
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