Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration

By W. S. Hambright, R. S. Fonseca, Liuji Chen, Ren Na, Qitao Ran. Redox Biology, 2017

753 citations recorded by the source corpus.

Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD.

Subfields: Molecular Biology, Neurology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/02c503e49dec76cca905c0a11af57a0313f66715

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Citations in the corpus

Ferroptosis: mechanisms and links with diseases (2021, background): “Targeted conditional knockout of GPx4 in forebrain neurons of adult mice causes AD-like cognitive impairments and neurodegeneration that can be attenuated by ferroptosis inhibitors.(245) Also, the expression of GPx4 might play a neuroprotective role in PD pathology.”
NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases (2021, background): “The features of ferroptosis, such as iron dysregulation, lipid peroxidation and inflammation, are important pathological events of AD and cognitive dysfunction [52].”
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Use of Cu chelators can inhibit ROS production triggered by Cu-Aβ, and reversed episodic memory impairment in non-transgenic AD mice [538, 541].”
Molecular mechanisms of cell death in neurological diseases (2021, background): “Vitamin E prevents the rapid death of neurons in conditional neuronal Gpx4 knockout mice [113, 114], whereas overexpression of GPX4 protects against intracerebral haemorrhage in rats [115].”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
Neuronal Cell Death. (2018, positive): “Conditional deletion of Gpx4 in forebrain neurons resulted in neurodegeneration and cognitive dysfunction (273).”
GPx4, Lipid Peroxidation, and Cell Death: Discoveries, Rediscoveries, and Open Issues (2017, positive): “1), these critical observations could then be expanded to parvalbumin-positive interneurons (114), photoreceptor cells (107), cerebellar Purkinje cells and granular cells (113), as well as motor neurons (19) and forebrain neurons (46).”
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. (2017, positive): “PUFAs, which are particularly enriched in brain, liver, testes, and kidney (Friedmann Angeli et al., 2014; Hambright et al., 2017), are essential and have afforded an increased repertoire of cellular and physiological functions, such as membrane fluidity, plasticity, neuronal network development, mi”
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. (2017, positive): “…Huntington´s, and Alzheimer´s Diseases, as well as in other forms of neurodegeneration and traumatic and hemorrhagic brain injury (Chen et al., 2015; Do Van et al., 2016; Gascon et al., 2016; Guiney et al., 2017; Hambright et al., 2017; Li et al., 2017; Skouta et al., 2014; Zille et al., 2017).”