Implication of ferroptosis iron‐dependent programmed cell death mechanism in neurodegeneration

Abstract Background Besides the abnormal accumulation of hyperphosphorylated tau, amyloid‐β plaques and neuroinflammation, progressive synaptic loss and neuronal cell death are persistent pathological hallmarks related to the development of neurodegeneration. However, the cellular pathways/mechanisms that trigger neuronal death in AD remain largely undefined. A detailed understanding and description of the molecular mechanisms related to neuronal loss processes in affected AD will be invaluable to the identification and development of new effective therapeutic targets. A novel form of iron‐dependent regulated cell death process termed ferroptosis was recently identified. Misregulated ferroptosis pathways have been speculated to trigger neurodegeneration, but the cellular mechanisms and signaling are not completely understood. Method Differentiated neurons were treated (0‐200uM) with different ferroptosis inductors or ferroptosis inductors+inhibitors to determine molecular responses. We employed analytical and advanced imaging techniques, including bioassays, transcriptomics, optical/confocal/electron microscopy and mass spectrometry to determine and compare cell responses, pathways and other features characteristic of ferroptosis. Then AD brain tissues were analyzed to image ferroptotic cells and transcriptomic profiles of pathways altered in ferroptosis. Result Some of the ferroptosis‐like biochemical and morphological features have been observed in AD: glutathione reduction, alterations in glutamate/cystine antiporter (X c ‐ ), lipid peroxidation, mitochondrial dysfunction, MAPK/ERK activation, GPX4 downregulation, and altered redox homeostasis. We determined that ferroptosis is activated in AD as a probable mechanism underlying neuronal loss in neurodegeneration, describing the mechanisms and cellular pathways involved. The results obtained showed alterations in cystine‐glutamate exhcnage, iron metabolism, glutathione metabolism and mevalonate pathway in neurons treated with ferroptosis inductors, particularly correlating with high oxidative stress and neuronal death, these responses were ameliorated when ferroptosis inhibitors were added to the neurons. These observations of altered ferroptosis were confirmed in AD brain and by determining their transcriptomic profiles of ferroptotic pathways. Conclusion Determine the molecular mechanisms related to ferroptosis in neuronal cells. Remarkably, the experimental approach allowed ( 1 ) establish a relationship between neuronal death and neurodegeneration in the context of ferroptosis, ( 2 ) impact our understanding of the AD pathogenesis and cell death mechanisms, and ( 3 ) determine novel strategies for early diagnosis and therapeutic interventions that target the molecular pathways of ferroptosis.