Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration
Open accessAbstract
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. • A novel mouse model with conditional ablation of Gpx4 in forebrain neurons was generated. • Conditional ablation of Gpx4 in forebrain neurons resulted in progressive cognition impairment. • The cognitively impaired mice with Gpx4 ablation in forebrain neurons showed neurodegeneration in hippocampus. • Neurodegeneration in mice with Gpx4 ablation in forebrain neurons exhibited features of ferroptosis.
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Inducible or tissue-specific ablation of Gpx4 in mice provokes acute renal or hepatic injury, neurodegeneration, and defective immunity to infection, all preventable or mitigated by ferroptosis-inhibiting strategies.
“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including 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.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [590]
Cu2+ chelators inhibit ROS production triggered by Cu-Aβ and reverse episodic memory impairment in non-transgenic AD mice.
“Use of Cu2+ chelators can inhibit ROS production triggered by Cu-Aβ, and reversed episodic memory impairment in non-transgenic AD mice [538, 541].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [541]
Iron affects lipid peroxidation through interactions with iron-dependent oxidases such as lipoxygenase, subsequently activating ferroptosis to accelerate AD progression.
“Iron can affect lipid peroxidation through interactions with iron-dependent oxidases such as lipoxygenase, subsequently activating ferroptosis to accelerate AD progression [541, 546, 547].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [541]
The features of ferroptosis, such as iron dysregulation, lipid peroxidation, and inflammation, are important pathological events of Alzheimer's disease and cognitive dysfunction.
“The features of ferroptosis, such as iron dysregulation, lipid peroxidation and inflammation, are important pathological events of AD and cognitive dysfunction [52].”
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- Authors
- Hambright, W. S., Fonseca, R. S., Chen, L., Na, R., & Ran, Q.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Ran, Qitao
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 12
- Pages
- 8-17
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC5312549
- OpenAlex
- W2583631769
- Cited by
- 851
- References
- 32
- Citations by year
- 2026: 90 · 2025: 102 · 2024: 133 · 2023: 120 · 2022: 129 · 2021: 106 · 2020: 71 · 2019: 50 · 2018: 36 · 2017: 13
- FWCI
- 38.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Department of Veteran Affairs (I01BX1382)
- Alzheimer's Association (IIRG-12-242388)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- ferroptosis, GPX4, forebrain neurons, hippocampal neurodegeneration, cognitive impairment, Alzheimer's disease, lipid peroxidation, ERK activation, neuroinflammation, vitamin E deficiency, ferroptosis inhibitors, spatial learning and memory, oxidative cell death
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Disease Models, Animal, Glutathione Peroxidase, Neurons, Oxidation-Reduction, Tamoxifen, Lipid Peroxidation, Prosencephalon, Cell Death, Maze Learning, Neurodegenerative Diseases, Mice, Gene Knockout Techniques, Cognitive Dysfunction
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