Expression data from Saccharomyces cerevisiae

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. 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 prone to form oligomers and toxic. Humanized yeast models are currently applied to unravel the cellular mechanisms behind Aβ toxicity. Here, we took a systems biology approach to study two yeast AD models which expressed either Aβ40 or Aβ42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected the chronological lifespan and reduced confounding effects of variations during cell growth. Reduced growth rates and biomass yields were observed upon expression of Aβ42, 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 fragmented mitochondrial structures. Genome-wide expression levels analysis showed that Aβ42 expression triggers strong ER stress and unfolded protein responses (UPR). Expression of Aβ40 induced only mild ER stress, leading to activation of UPR target genes that cope with misfolded proteins, which resulted in hardly affected physiology. The combination of well-controlled cultures and AD yeast models strengthen our understanding of how cells translate different levels of Aβ toxicity signals into particular cell fate programs, and further enhance their role as a discovery platform to identify potential therapies.阿尔茨海默病（Alzheimer’s disease, AD）是一种进行性神经退行性疾病。β淀粉样肽（Amyloid-β peptides, Aβ）寡聚体被认为在AD发病机制中发挥关键作用，但其相关调控机制仍未明确。与AD相关的Aβ主要存在两种亚型：Aβ40与Aβ42，其中Aβ42更易形成寡聚体且毒性更强。当前研究多采用人源化酵母模型来解析Aβ毒性背后的细胞分子机制。本研究采用系统生物学方法，对两种分别表达Aβ40或Aβ42的酵母AD模型开展生物反应器培养研究。本研究严格控制培养体系的氧气供应与培养液pH，此举不仅显著调控了细胞时序寿命，同时有效降低了细胞生长过程中变量带来的混杂效应。研究观察到，表达Aβ42的酵母菌株生长速率与生物量得率均出现显著下降，提示细胞将能量代谢从生长增殖转向了维持存活。定量生理学分析进一步揭示，表达Aβ42的细胞线粒体功能与三磷酸腺苷（ATP）生成能力均出现降低，这与观测到的异常碎片化线粒体结构高度吻合。全基因组表达水平分析显示，Aβ42的表达会强烈触发内质网应激与未折叠蛋白反应（unfolded protein responses, UPR）；而Aβ40的表达仅会引发轻度内质网应激，仅激活负责清除错误折叠蛋白的UPR靶基因，因此其生理状态几乎未受影响。本研究结合严格可控的培养体系与酵母AD模型，加深了我们对细胞如何将不同水平的Aβ毒性信号转化为特定细胞命运程序的理解，并进一步强化了此类模型作为潜在治疗靶点发现平台的应用价值。