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NRF2 Deficiency Promotes Ferroptosis of Astrocytes Mediated by Oxidative Stress in Alzheimer’s Disease

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Abstract

Oxidative stress is involved in the pathogenesis of Alzheimer’s disease (AD), which is linked to reactive oxygen species (ROS), lipid peroxidation, and neurotoxicity. Emerging evidence suggests a role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major source of antioxidant response elements in AD. The molecular mechanism of oxidative stress and ferroptosis in astrocytes in AD is not yet fully understood. Here, we aimed to investigate the mechanism by which Nrf2 regulates the ferroptosis of astrocytes in AD. We found decreased expression of Nrf2 and upregulated expression of the ROS marker NADPH oxidase 4 (NOX4) in the frontal cortex from patients with AD and in the cortex of 3×Tg mice compared to wildtype mice. We demonstrated that Nrf2 deficiency led to ferroptosis-dependent oxidative stress-induced ROS with downregulated heme oxygenase-1 and glutathione peroxidase 4 and upregulated cystine glutamate expression. Moreover, Nrf2 deficiency increased lipid peroxidation, DNA oxidation, and mitochondrial fragmentation in mouse astrocytes (mAS, M1800-57). In conclusion, these results suggest that Nrf2 deficiency promotes ferroptosis of astrocytes involving oxidative stress in AD.

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References

  1. De Strooper B, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164(4):603–615

    Article  PubMed  Google Scholar 

  2. Wilson DM 3rd, Cookson MR, Van Den Bosch L et al (2023) Hallmarks of neurodegenerative diseases. Cell 186(4):693–714

    Article  CAS  PubMed  Google Scholar 

  3. Brandebura AN, Paumier A, Onur TS et al (2023) Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci 24(1):23–39

    Article  CAS  PubMed  Google Scholar 

  4. Escartin C, Galea E, Lakatos A et al (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 24(3):312–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hasel P, Rose IVL, Sadick JS et al (2021) Neuroinflammatory astrocyte subtypes in the mouse brain. Nat Neurosci 24(10):1475–1487

    Article  CAS  PubMed  Google Scholar 

  6. Habib N, McCabe C, Medina S et al (2020) Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci 23(6):701–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kecheliev V, Spinelli F, Herde A et al (2022) Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease. Front Aging Neurosci 14:1018610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rodriguez-Vieitez E, Ni R, Gulyás B et al (2015) Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging 42(7):1119–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20(3):148–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cheignon C, Tomas M, Bonnefont-Rousselot D et al (2018) Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14:450–464

    Article  CAS  PubMed  Google Scholar 

  11. Cioffi F, Adam RHI, Bansal R et al (2021) A review of oxidative stress products and related genes in early Alzheimer’s disease. J Alzheim Dis : JAD 83(3):977–1001

    Article  CAS  Google Scholar 

  12. Ionescu-Tucker A, Cotman CW (2021) Emerging roles of oxidative stress in brain aging and Alzheimer’s disease. Neurobiol Aging 107:86–95

    Article  CAS  PubMed  Google Scholar 

  13. Nunomura A, Perry G (2020) RNA and oxidative stress in Alzheimer’s disease: focus on microRNAs. Oxid Med Cell Longev 2020:2638130

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bonda DJ, Wang X, Lee HG et al (2014) Neuronal failure in Alzheimer’s disease: a view through the oxidative stress looking-glass. Neurosci Bull 30(2):243–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Perez Ortiz JM, Swerdlow RH (2019) Mitochondrial dysfunction in Alzheimer’s disease: role in pathogenesis and novel therapeutic opportunities. Br J Pharmacol 176(18):3489–3507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wood H (2020) Mitochondrial dysfunction manifests in the early stages of Alzheimer disease. Nat Rev Neurol 16(5):242

    CAS  PubMed  Google Scholar 

  17. Chiang MC, Nicol CJB (2022) GSH-AuNP anti-oxidative stress, ER stress and mitochondrial dysfunction in amyloid-beta peptide-treated human neural stem cells. Free Radical Biol Med 187:185–201

    Article  CAS  Google Scholar 

  18. Cheignon C, Jones M, Atrián-Blasco E et al (2017) Identification of key structural features of the elusive Cu-Aβ complex that generates ROS in Alzheimer’s disease. Chem Sci 8(7):5107–5118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gleason A, Bush AI (2021) Iron and ferroptosis as therapeutic targets in Alzheimer’s disease. Neurotherap :J Am Soc Exp NeuroTherap 18(1):252–264

    Article  Google Scholar 

  20. Li J, Cao F, Yin HL et al (2020) Ferroptosis: past, present and future. Cell Death Dis 11(2):88

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yan HF, Zou T, Tuo QZ et al (2021) Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 6(1):49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jakaria M, Belaidi AA, Bush AI et al (2021) Ferroptosis as a mechanism of neurodegeneration in Alzheimer’s disease. J Neurochem 159(5):804–825

    Article  CAS  PubMed  Google Scholar 

  23. Galluzzi L, Vitale I, Aaronson SA et al (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25(3):486–541

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tang D, Chen X, Kang R et al (2021) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125

    Article  CAS  PubMed  Google Scholar 

  25. Zhang J, Wang X, Guan B et al (2023) Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway. J Ethnopharmacol 301:115852

    Article  CAS  PubMed  Google Scholar 

  26. Wang Z, Ding Y, Wang X et al (2018) Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT. Cancer Lett 428:21–33

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Z, Tang J, Song J et al (2022) Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling. Free Radical Biol Med 181:130–142

    Article  CAS  Google Scholar 

  28. Bersuker K, Hendricks JM, Li Z et al (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784):688–692

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ashraf A, Jeandriens J, Parkes HG et al (2020) Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: evidence of ferroptosis. Redox Biol 32:101494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Friedmann Angeli JP, Schneider M, Proneth B et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191

    Article  CAS  PubMed  Google Scholar 

  31. Skouta R, Dixon SJ, Wang J et al (2014) Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 136(12):4551–4556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Park MW, Cha HW, Kim J et al (2021) NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases. Redox Biol 41:101947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Johnson J, Mercado-Ayon E, Mercado-Ayon Y et al (2021) Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Arch Biochem Biophys 702:108698

    Article  CAS  PubMed  Google Scholar 

  34. Dinkova-Kostova AT, Kostov RV, Kazantsev AG (2018) The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS J 285(19):3576–3590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Osama A, Zhang J, Yao J et al (2020) Nrf2: a dark horse in Alzheimer’s disease treatment. Ageing Res Rev 64:101206

    Article  CAS  PubMed  Google Scholar 

  36. Qu Z, Sun J, Zhang W et al (2020) Transcription factor NRF2 as a promising therapeutic target for Alzheimer’s disease. Free Radical Biol Med 159:87–102

    Article  CAS  Google Scholar 

  37. Lipton SA, Rezaie T, Nutter A et al (2016) Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death Dis 7(12):e2499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Adlimoghaddam A, Odero GG, Glazner G et al (2021) Nilotinib improves bioenergetic profiling in brain astroglia in the 3xTg mouse model of Alzheimer’s disease. Aging Dis 12(2):441–465

    Article  PubMed  PubMed Central  Google Scholar 

  39. Esteras N, Dinkova-Kostova AT, Abramov AY (2016) Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function. Biol Chem 397(5):383–400

    Article  CAS  PubMed  Google Scholar 

  40. Johnson DA, Johnson JA (2015) Nrf2–a therapeutic target for the treatment of neurodegenerative diseases. Free Radical Biol Med 88(Pt B):253–267

    Article  CAS  Google Scholar 

  41. Sotolongo K, Ghiso J, Rostagno A (2020) Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage. Alzheim Res Ther 12(1):13

    Article  CAS  Google Scholar 

  42. Bahn G, Park JS, Yun UJ et al (2019) NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models. Proc Natl Acad Sci USA 116(25):12516–12523

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Oddo S, Caccamo A, Shepherd JD et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421

    Article  CAS  PubMed  Google Scholar 

  44. Ni R, Röjdner J, Voytenko L et al (2021) In vitro characterization of the regional binding distribution of amyloid PET tracer florbetaben and the glia tracers deprenyl and PK11195 in autopsy Alzheimer’s brain tissue. J Alzheim Dis: JAD 80(4):1723–1737

    Article  CAS  Google Scholar 

  45. Ni R, Gillberg PG, Bogdanovic N et al (2017) Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer’s disease. Alzheim Demen : J Alzheim Assoc 13(4):419–430

    Article  Google Scholar 

  46. Lai C, Chen Z, Ding Y et al (2022) Rapamycin attenuated zinc-induced tau phosphorylation and oxidative stress in rats: involvement of dual mTOR/p70S6K and Nrf2/HO-1 pathways. Front Immunol 13:782434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang L, Tang Z, Deng Y et al (2023) Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways. bioRxiv 2023.01.12.523781

  48. Tang Z, Guo M, Peng Y et al (2022) Quercetin reduces APP expression, oxidative stress and mitochondrial dysfunction in the N2a/APPswe cells via ERK1/2 and AKT pathways. bioRxiv 2022.09.18.508406

  49. Chen Q, Lai C, Chen F et al (2022) Emodin protects SH-SY5Y cells against zinc-induced synaptic impairment and oxidative stress through the ERK1/2 pathway. Front Pharmacol 13:821521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li Y, Zhao T, Li J et al (2022) Oxidative stress and 4-hydroxy-2-nonenal (4-HNE): implications in the pathogenesis and treatment of aging-related diseases. J Immunol Res 2022:2233906

    PubMed  PubMed Central  Google Scholar 

  51. Angelova PR, Abramov AY (2018) Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Lett 592(5):692–702

    Article  CAS  PubMed  Google Scholar 

  52. Tönnies E, Trushina E (2017) Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheim Dis: JAD 57(4):1105–1121

    Article  Google Scholar 

  53. Resende R, Moreira PI, Proença T et al (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radical Biol Med 44(12):2051–2057

    Article  CAS  Google Scholar 

  54. Matsumura A, Emoto MC, Suzuki S et al (2015) Evaluation of oxidative stress in the brain of a transgenic mouse model of Alzheimer disease by in vivo electron paramagnetic resonance imaging. Free Radical Biol Med 85:165–173

    Article  CAS  Google Scholar 

  55. Stefanatos R, Sanz A (2018) The role of mitochondrial ROS in the aging brain. FEBS Lett 592(5):743–758

    Article  CAS  PubMed  Google Scholar 

  56. Pareek V, Nath B, Roy PK (2019) Role of neuroimaging modality in the assessment of oxidative stress in brain: a comprehensive review. CNS Neurol Disord: Drug Targets 18(5):372–381

    Article  CAS  PubMed  Google Scholar 

  57. Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Aborode AT, Pustake M, Awuah WA et al (2022) Targeting oxidative stress mechanisms to treat Alzheimer’s and Parkinson’s disease: a critical review. Oxid Med Cell Longev 2022:7934442

    Article  PubMed  PubMed Central  Google Scholar 

  59. Anwar MM (2022) Oxidative stress-A direct bridge to central nervous system homeostatic dysfunction and Alzheimer’s disease. Cell Biochem Funct 40(1):17–27

    Article  CAS  PubMed  Google Scholar 

  60. Francesca F, Caitlin A, Sarah L et al (2022) Antroquinonol administration in animal preclinical studies for Alzheimer’s disease (AD): a new avenue for modifying progression of AD pathophysiology. Brain, Behav Immun Health 21:100435

    Article  CAS  PubMed  Google Scholar 

  61. Tao W, Yu L, Shu S et al (2021) miR-204-3p/Nox4 mediates memory deficits in a mouse model of Alzheimer’s disease. Mole Ther : J Am Soc Gene Ther 29(1):396–408

    Article  CAS  Google Scholar 

  62. Chun H, Im H, Kang YJ et al (2020) Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H(2)O(2)(-) production. Nat Neurosci 23(12):1555–1566

    Article  CAS  PubMed  Google Scholar 

  63. Guillemaud O, Ceyzériat K, Saint-Georges T et al (2020) Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease. Neurobiol Aging 90:135–146

    Article  CAS  PubMed  Google Scholar 

  64. Jiwaji Z, Tiwari SS, Avilés-Reyes RX et al (2022) Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nat Commun 13(1):135

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bellaver B, Povala G, Ferreira PCL, et al. Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease. Nature medicine. 2023.

  66. Xu S, Wu B, Zhong B et al (2021) Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) /System xc-/ glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis. Bioengineered 12(2):10924–10934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Feng Y, Wang X (2012) Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev 2012:472932

    Article  PubMed  PubMed Central  Google Scholar 

  68. Zeng K, Yu X, Mahaman YAR et al (2022) Defective mitophagy and the etiopathogenesis of Alzheimer’s disease. Transl Neurodegen 11(1):32

    Article  Google Scholar 

  69. Su B, Wang X, Nunomura A et al (2008) Oxidative stress signaling in Alzheimer’s disease. Curr Alzheimer Res 5(6):525–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dixon SJ, Patel DN, Welsch M et al (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3:e02523

    Article  PubMed  PubMed Central  Google Scholar 

  71. Chen X, Yu C, Kang R et al (2021) Cellular degradation systems in ferroptosis. Cell Death Differ 28(4):1135–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li K, Reichmann H (2016) Role of iron in neurodegenerative diseases. J Neural Transm 123(4):389–399

    Article  CAS  PubMed  Google Scholar 

  74. Tu H, Tang LJ, Luo XJ et al (2021) Insights into the novel function of system Xc- in regulated cell death. Eur Rev Med Pharmacol Sci 25(3):1650–1662

    CAS  PubMed  Google Scholar 

  75. Stockwell BR, Friedmann Angeli JP, Bayir H et al (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171(2):273–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Conrad M, Kagan VE, Bayir H et al (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32(9–10):602–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Liu M, Kong XY, Yao Y et al (2022) The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review. Ann Transl Med 10(6):368

    Article  PubMed  PubMed Central  Google Scholar 

  78. Su LJ, Zhang JH, Gomez H et al (2019) Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev 2019:5080843

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ursini F, Maiorino M (2020) Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radical Biol Med 152:175–185

    Article  CAS  Google Scholar 

  80. Park E, Chung SW (2019) ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death Dis 10(11):822

    Article  PubMed  PubMed Central  Google Scholar 

  81. Mecocci P, Boccardi V, Cecchetti R et al (2018) A long journey into aging, brain aging, and Alzheimer’s disease following the oxidative stress tracks. J Alzheim Dis: JAD 62(3):1319–1335

    Article  Google Scholar 

  82. Nunomura A, Perry G, Pappolla MA et al (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci :J Soc Neurosci 19(6):1959–1964

    Article  CAS  Google Scholar 

  83. Gómez-Pineda VG, Torres-Cruz FM, Vivar-Cortés CI et al (2018) Neurotrophin-3 restores synaptic plasticity in the striatum of a mouse model of Huntington’s disease. CNS Neurosci Ther 24(4):353–363

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ren P, Chen J, Li B et al (2020) Nrf2 ablation promotes Alzheimer’s disease-like pathology in APP/PS1 transgenic mice: the role of neuroinflammation and oxidative stress. Oxid Med Cell Longev 2020:3050971

    Article  PubMed  PubMed Central  Google Scholar 

  85. Branca C, Ferreira E, Nguyen TV et al (2017) Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. Hum Mol Genet 26(24):4823–4835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Uruno A, Matsumaru D, Ryoke R, et al. Nrf2 suppresses oxidative stress and inflammation in app knock-in Alzheimer’s disease model mice. Molecular and cellular biology. 2020;40(6).

  87. Abdalkader M, Lampinen R, Kanninen KM et al (2018) Targeting Nrf2 to suppress ferroptosis and mitochondrial dysfunction in neurodegeneration. Front Neurosci 12:466

    Article  PubMed  PubMed Central  Google Scholar 

  88. Liddell JR. Are astrocytes the predominant cell type for activation of Nrf2 in aging and neurodegeneration? Antioxidants. 2017;6(3).

  89. Wang W, Zhao F, Ma X et al (2020) Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Mol Neurodegener 15(1):30

    Article  PubMed  PubMed Central  Google Scholar 

  90. Sorrentino V, Romani M, Mouchiroud L et al (2017) Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 552(7684):187–193

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ashleigh T, Swerdlow RH, Beal MF (2023) The role of mitochondrial dysfunction in Alzheimer’s disease pathogenesis. Alzheim Dement 19(1):333–342

    Article  CAS  Google Scholar 

  92. Dhapola R, Sarma P, Medhi B et al (2022) Recent advances in molecular pathways and therapeutic implications targeting mitochondrial dysfunction for Alzheimer’s disease. Mol Neurobiol 59(1):535–555

    Article  CAS  PubMed  Google Scholar 

  93. Zhu CC, Fu SY, Chen YX et al (2020) Advances in drug therapy for Alzheimer’s disease. Curr Med Sci 40(6):999–1008

    Article  CAS  PubMed  Google Scholar 

  94. Jackson JG, Robinson MB (2018) Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns. Glia 66(6):1213–1234

    Article  PubMed  Google Scholar 

  95. Joshi AU, Minhas PS, Liddelow SA et al (2019) Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci 22(10):1635–1648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hung CH, Cheng SS, Cheung YT et al (2018) A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration. Redox Biol 14:7–19

    Article  CAS  PubMed  Google Scholar 

  97. Dematteis G, Vydmantaitė G, Ruffinatti FA et al (2020) Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice. Cell Death Dis 11(8):645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Li Q, Han X, Lan X et al (2017) Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI insight 2(7):e90777

    Article  PubMed  PubMed Central  Google Scholar 

  99. Liddell JR, White AR (2018) Nexus between mitochondrial function, iron, copper and glutathione in Parkinson’s disease. Neurochem Int 117:126–138

    Article  CAS  PubMed  Google Scholar 

  100. Joshi G, Gan KA, Johnson DA et al (2015) Increased Alzheimer’s disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36(2):664–679

    Article  CAS  PubMed  Google Scholar 

  101. Liu Z, Han K, Huo X et al (2020) Nrf2 knockout dysregulates iron metabolism and increases the hemolysis through ROS in aging mice. Life Sci 255:117838

    Article  CAS  PubMed  Google Scholar 

  102. Lai C, Chen Q, Ding Y et al (2020) Emodin protected against synaptic impairment and oxidative stress induced by fluoride in SH-SY5Y cells by modulating ERK1/2/Nrf2/HO-1 pathway. Environ Toxicol 35(9):922–929

    Article  ADS  CAS  PubMed  Google Scholar 

  103. Sumien N, Cunningham JT, Davis DL, et al. Neurodegenerative disease: roles for sex, hormones, and oxidative stress. Endocrinology. 2021;162(11).

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Funding

This work was supported by the Chinese National Natural Science Foundation (81960265, 82260263), the China Postdoctoral Science Foundation (2020M683659XB), the Foundation for Guizhou Provincial Science and Technology projects ([2020]1Y354 and [2023]232), the Department of Education of Guizhou Province [Nos. KY (2021)313], the Scientific Research Project of Guizhou Medical University (J[48]), and the Foundation for Science and Technology projects in Guiyang ([2019]9–2-7).

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  1. Zhi Tang and Zhuyi Chen contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, 550004, China

    Zhi Tang, Zhuyi Chen, Min Guo, Yaqian Peng, Yan Xiao, Zhizhong Guan & Xiaolan Qi

  2. Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou, 550004, China

    Zhizhong Guan

  3. Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland

    Ruiqing Ni

  4. Institute for Biomedical Engineering, ETH Zurich and University of Zurich, Zurich, Switzerland

    Ruiqing Ni

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  1. Zhi Tang
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Contributions

Conceptualization ZT, RN, and XLQ; data curation, investigation, formal analysis: ZYC, ZT, and YX; supervision, resources, project administration: RN and ZT; Original draft: XLQ, ZYC, RN, and ZT; review and editing: all authors.

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Correspondence to Ruiqing Ni or Xiaolan Qi.

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The study of human brain tissues was conducted according to the principles of the Declaration of Helsinki and subsequent revisions and ethical permission obtained from the regional human ethics committee in Guiyang Hospital (approval No. 2022290) and the medical ethics committee of the VU Medical Center for NBB tissue. And all the animal experiments were performed in accordance with guidelines under the approval of the Animal Protection and Use Committee of Guizhou Medical University (approval No. 2201640).

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Tang, Z., Chen, Z., Guo, M. et al. NRF2 Deficiency Promotes Ferroptosis of Astrocytes Mediated by Oxidative Stress in Alzheimer’s Disease. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04023-9

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