Effects of intracellular amyloid toxicity on the transcriptome of MC65 human nerve cells

Amyloid beta (Aß) accumulates within neurons in the brains of early stage Alzheimer's disease (AD) patients. However, the mechanism underlying its potential toxicity remains unclear. To elucidate this, a transcriptomic study was carried out using a nerve cell model of toxic intracellular aggregation of Aß. The neuroprotective compound CMS121 was included as a validating tool. It was found that intracellular Aß induces profound changes in the omics landscape of nerve cells that are associated with a cancer-like metabolic reprogramming, the oxytosis/ferroptosis cell death program, and physiological alterations detrimental to mitochondrial function. Our findings have implications for the understanding of the basic biology of proteotoxicity, aging and AD as well as for the development of future therapeutic interventions designed to target the oxytosis/ferroptosis programmed cell death pathway in the AD brain. Overall design: We carried out a study of the whole transcriptome of human MC65 nerve cells in conditions of non-induced and induced Aß toxicity in the absence and presence of 1uM CMS121. The MC65 is a human nerve cell line that contains the C99 fragment of the amyloid precursor protein (APP) under the control of a tetracycline-sensitive promoter. The parent cell line is SK-N-MC from a human neuroblastoma, and it has an electrically excitable membrane typical of neurons. When tetracycline is withdrawn, MC65 nerve cells express C99 that is converted to Aß by ?-secretase and the cells die within 3 days due to Aß accumulation and aggregation within cells. In our study, cells were harvested at day 2 after Aß induction, prior to any cell death, and the whole RNA was isolated and sequenced.