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Cited by 73Alzheimer's disease research and treatmentsFerroptosis and cancer prognosisNeurological diseases and metabolism

The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression

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Majerníková, Naďa, Marmolejo-Garza, Alejandro, Salinas, Casandra Salinas, Luu, Minh D. A., Zhang, Yuequ, Trombetta-Lima, Marina, Tomin, Tamara, Birner-Gruenberger, Ruth +6 more·2024·Cell Death & Disease
DOI 10.1038/s41419-024-07152-0PMC PMC11519607
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Abstract

Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

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  1. [1]Gaugler J, James B, Johnson T, Scholz K, Weuve J. Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2016;18:700–89. 35289055
  2. [2]Yiannopoulou KG, Anastasiou AI, Zachariou V, Pelidou SH. Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research. Biomedicines. 2019;7:97. 31835422 PMC6966425 · DOI · Paper page
  3. [3]Obulesu M, Lakshmi MJ. Apoptosis in Alzheimer’s disease: an understanding of the physiology, pathology and therapeutic avenues. Neurochem Res. 2014;39:2301–12. 25322820 · DOI
  4. [4]Tanaka H, Homma H, Fujita K, Kondo K, Yamada S, Jin X, et al. YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology. Nat Commun. 2020;11:507. 31980612 PMC6981281 · DOI · Paper page
  5. [5]Li Q, Sun M. The role of autophagy in Alzheimer’s disease. J Syst Integr Neurosci. 2017;3:1–6. · DOI
  6. [6]Marmolejo-Garza A, Medeiros-Furquim T, Rao R, Eggen BJL, Boddeke E, Dolga AM. Transcriptomic and epigenomic landscapes of Alzheimer’s disease evidence mitochondrial-related pathways. Biochim Biophys Acta Mol Cell Res. 2022;1869:119326. 35839870 · DOI
  7. [7]Trombetta-Lima M, Sabogal-Guáqueta AM, Dolga AM. Mitochondrial dysfunction in neurodegenerative diseases: a focus on iPSC-derived neuronal models. Cell Calcium. 2021;94:102362. 33540322 · DOI
  8. [8]Granic I, Dolga AM, Nijholt IM, Van Dijk G, Eisel ULM. Inflammation and NF-κB in Alzheimer’s disease and diabetes. J Alzheimer’s Dis. 2009;16:809–21. 19387114 · DOI
  9. [9]Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31:107–25. 33268902 PMC8026611 · DOI
  10. [10]Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. 22632970 PMC3367386 · DOI · Paper page
  11. [11]Jakaria M, Belaidi AA, Bush AI, Ayton S. Ferroptosis as a mechanism of neurodegeneration in Alzheimer’s disease. J Neurochem. 2021;159:804–25. 34553778 · DOI
  12. [12]Ayton S, Fazlollahi A, Bourgeat P, Raniga P, Ng A, Lim YY, et al. Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline. Brain. 2017;140:2112–9. 28899019 · DOI
  13. [13]Peña-Bautista C, Baquero M, Vento M, Cháfer-Pericás C. Free radicals in Alzheimer’s disease: Lipid peroxidation biomarkers. Clin Chim Acta. 2019;491:85–90. 30685358 · DOI
  14. [14]Majerníková N, Jia J, Andrea Y. CuATSM PET to diagnose age-related diseases: a systematic literature review. Clin Transl Imaging. 2020;8:449–60. · DOI
  15. [15]Majerníková N, den Dunnen WFA, Dolga AM. The potential of ferroptosis-targeting therapies for Alzheimer’s disease: from mechanism to transcriptomic analysis. Front Aging Neurosci. 2021;13:1–14. PMC8721139 34987375 · DOI
  16. [17]Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–7. 31042697 PMC6865822 · DOI · Paper page
  17. [20]Jellinger K, Bancher C. Neuropathology of Alzheimer’s disease: a critical update. J Neural Transm Suppl. 1998;54:77–95. 9850917 · DOI
  18. [21]Peñaranda-Fajardo NM, Meijer C, Liang Y, Dijkstra BM, Aguirre-Gamboa R, den Dunnen WFA, et al. ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation. Cell Death Dis. 2019;10:1–16. PMC6751174 31534165 · DOI
  19. [22]Zois CE, Hendriks AM, Haider S, Pires E, Bridges E, Kalamida D, et al. Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation. Cell Death Dis. 2022;13:573. 35764612 PMC9240045 · DOI
  20. [23]Leng K, Li E, Eser R, Piergies A, Sit R, Tan M, et al. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat Neurosci. 2021;24:276–87. 33432193 PMC7854528 · DOI · Paper page
  21. [24]Ferrari SLP, Cribari-Neto F. Beta regression for modelling rates and proportions. J Appl Stat. 2010;31:799–815. · DOI · Paper page
  22. [26]Gunhanlar N, Shpak G, van der Kroeg M, Gouty-Colomer LA, Munshi ST, Lendemeijer B, et al. A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells. Mol Psychiatry. 2018;23:1336–44. 28416807 PMC5984104 · DOI
  23. [27]Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72. 19029910 · DOI · Paper page
  24. [28]Tyanova S, Temu T, Cox J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat Protoc. 2016;11:2301–19. 27809316 · DOI
  25. [29]Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016;13:731–40. 27348712 · DOI
  26. [30]Sambo D, Li J, Brickler T, Chetty S. Transient treatment of human pluripotent stem cells with dmso to promote differentiation. J Vis Exp. 2019;149:e59833. 31380840
  27. [31]Sabogal-Guaqueta AM, Marmolejo-garza A, Trombetta M, Oun A, Hunneman J, Chen T, et al. Species-specific metabolic reprogramming in human and mouse microglia during 2 inflammatory pathway induction. Nat Commun. 2023;14:6454. 37833292 PMC10575978 · DOI
  28. [32]Perez-Riverol Y, Bai J, Bandla C, García-Seisdedos D, Hewapathirana S, Kamatchinathan S, et al. The PRIDE database resources in 2022: A hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2022;50:D543–52. 34723319 PMC8728295 · DOI · Paper page
  29. [34]Ayton S, Portbury S, Kalinowski P, Agarwal P, Diouf I, Schneider JA, et al. Regional brain iron associated with deterioration in Alzheimer’s disease: a large cohort study and theoretical significance. Alzheimer’s Dement. 2021;17:1244–56. 33491917 PMC9701539 · DOI
  30. [36]Stern N, Gacs A, Tátrai E, Flachner B, Hajdú I, Dobi K, et al. Dual inhibitors of AChE and BACE-1 for reducing Aβ in Alzheimer’s disease: from in silico to in vivo. Int J Mol Sci. 2022;23:13098. 36361906 PMC9655245 · DOI · Paper page
  31. [37]Frey AG, Nandal A, Park JH, Smith PM, Yabe T, Ryu MS, et al. Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci USA. 2014;111:8031–6. 24843120 PMC4050543 · DOI
  32. [38]Badhwar A, Brown R, Stanimirovic DB, Haqqani AS, Hamel E. Proteomic differences in brain vessels of Alzheimer’s disease mice: Normalization by PPARI 3 agonist pioglitazone. J Cereb Blood Flow Metab. 2017;37:1120–36. 27339263 PMC5363486 · DOI
  33. [39]Ayton S, Faux NG, Bush AI, Weiner MW, Aisen P, Petersen R, et al. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun. 2015;6:6760. 25988319 PMC4479012 · DOI
  34. [43]Biasiotto G, Di Lorenzo D, Archetti S, Zanella I. Iron and neurodegeneration: is ferritinophagy the link? Mol Neurobiol. 2016;53:5542–74. 26468157 · DOI
  35. [44]Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, et al. SRC-3Δ4 mediates the interaction of EGFR with FAK to promote cell migration. Mol Cell. 2009;37:321–32. PMC2824333 20159552 · DOI
  36. [45]De Wilde MC, Overk CR, Sijben JW, Masliah E. Meta-analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimer’s Dement. 2019;12:633–44. PMC5058345 26776762 · DOI
  37. [46]Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T, et al. Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson’s brain. Mol Neurodegener. 2011;6:8. 21255396 PMC3037910 · DOI
  38. [47]Daviaud N, Chevalier C, Friedel RH, Zou H. Distinct vulnerability and resilience of human neuroprogenitor subtypes in cerebral organoid model of prenatal hypoxic injury. Front Cell Neurosci. 2019;13:1–14. 31417360 PMC6682705 · DOI
  39. [48]Gabarró-Solanas R, Davaatseren A, Kepčija T, Crespo-Enríquez I, Urbán N. Adult neural stem cells and neurogenesis are resilient to intermittent fasting. bioRxiv. 2023;24:e57268. PMC10702802 37987220
  40. [49]Allodi I, Nijssen J, Benitez JA, Schweingruber C, Fuchs A, Bonvicini G, et al. Modeling motor neuron resilience in ALS using stem cells. Stem Cell Rep. 2019;12:1329–41. PMC6565614 31080111 · DOI
  41. [50]Cakir B, Tanaka Y, Kiral FR, Xiang Y, Dagliyan O, Wang J, et al. Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids. Nat Commun. 2022;13:430. 35058453 PMC8776770 · DOI
  42. [51]Yanatori I, Richardson DR, Toyokuni S, Kishi F. The new role of poly (rC)-binding proteins as iron transport chaperones: proteins that could couple with inter-organelle interactions to safely traffic iron. Biochim Biophys Acta Gen Subj. 2020;1864:129685. 32679248 · DOI
  43. [52]Key J, Sen NE, Arsović A, Krämer S, Hülse R, Khan NN, et al. Systematic surveys of iron homeostasis mechanisms reveal ferritin superfamily and nucleotide surveillance regulation to be modified by PINK1 absence. Cells. 2020;9:2229. 33023155 PMC7650593 · DOI
  44. [53]Richter M, Vidovic N, Biber K, Dolga A, Culmsee C, Dodel R. The neuroprotective role of microglial cells against amyloid beta-mediated toxicity in organotypic hippocampal slice cultures. Brain Pathol. 2020;30:589–602. 31769564 PMC8018096 · DOI
  45. [54]Sabogal-Guáqueta AM, Marmolejo-Garza A, de Pádua VP, Eggen B, Boddeke E, Dolga AM. Microglia alterations in neurodegenerative diseases and their modeling with human induced pluripotent stem cell and other platforms. Prog Neurobiol. 2020;190:101805. 32335273 · DOI
  46. [56]Delehouzé C, Comte A, Leon-Icaza SA, Cougoule C, Hauteville M, Goekjian P, et al. Nigratine as dual inhibitor of necroptosis and ferroptosis regulated cell death. Sci Rep. 2022;12:5118. 35332201 PMC8944179 · DOI
  47. [57]Zhang X, Ma Y, Ji J, Zhao X, Yuan J, Wang H, et al. High-fat diet alleviates colitis by inhibiting ferroptosis via solute carrier family seven member 11. J Nutr Biochem. 2022;109:109106. 35858667 · DOI

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Authors
Majerníková, N., Marmolejo-Garza, A., Salinas, C. S., Luu, M. D. A., Zhang, Y., Trombetta-Lima, M., Tomin, T., Birner-Gruenberger, R., Lehtonen, Š., Koistinaho, J., Wolters, J. C., Ayton, S., den Dunnen, W. F. A., & Dolga, A. M.
Affiliations
  • University Medical Center Groningen (NL)
  • University of Groningen (NL)
  • TU Wien (AT)
  • University of Helsinki (FI)
  • The University of Melbourne (AU)
Corresponding author
Dolga, Amalia M.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2024-10-28
Volume
15
Issue
10
Pages
782-782
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-024-07152-0
PMC
PMC11519607
OpenAlex
W4403826316
Cited by
73
References
10
Citations by year
2026: 51 · 2025: 21 · 2024: 1
FWCI
20.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
Alzheimer Nederland
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
Alzheimer's disease, amyloid-beta, ferroptosis, lipid peroxidation, iron accumulation, Nrf2, GPX4, brain organoids, iPSC-derived neurons, postmortem brain, gray and white matter, disease progression, ferroptosis inhibition
MeSH terms
Ferroptosis, Alzheimer Disease, Brain, Female, Humans, Iron, Male, Organoids, Lipid Peroxidation, Amyloid beta-Peptides, Disease Progression

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