Transcriptomic signatures of oxytosis/ferroptosis are enriched in Alzheimer's disease

Oxytosis/ferroptosis is a form of non-apoptotic regulated cell death characterized by specific changes in the redox balance that lead to lethal lipid peroxidation. It has been hypothesized recently that aging predisposes the brain to the activation of oxytosis/ferroptosis in Alzheimer's disease (AD), and consequently that inhibition of oxytosis/ferroptosis offers a path to develop a new class of therapeutics for the disease. The goal of the present study was to investigate the occurrence of oxytosis/ferroptosis in the AD brain by examining transcriptomic signatures of oxytosis/ferroptosis in cellular and animal models of AD as well as in human AD brain samples.

Since oxytosis/ferroptosis has been poorly defined at the RNA level, the publicly available datasets are limited. To address this limitation, we developed TrioSig, a gene signature generated from transcriptomic data of human microglia, astrocytes, and neurons treated with inducers of oxytosis/ferroptosis. It is shown that the different signatures of oxytosis/ferroptosis are enriched to varying extents in the brains of AD mice and human AD patients. The TrioSig signature was the most frequently found enriched, and bioinformatic analysis of its composition identified genes involved in the integrated stress response (ISR). It was confirmed in nerve cell culture that oxytosis/ferroptosis induces the ISR via phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and activating transcription factor 4 (ATF4) signaling.

Our data support the involvement of oxytosis/ferroptosis in AD. The implications of the ISR for the progression and prevention of AD are discussed.