The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression
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 eff...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07152-0 |
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| author | Naďa Majerníková Alejandro Marmolejo-Garza Casandra Salinas Salinas Minh D. A. Luu Yuequ Zhang Marina Trombetta-Lima Tamara Tomin Ruth Birner-Gruenberger Šárka Lehtonen Jari Koistinaho Justina C. Wolters Scott Ayton Wilfred F. A. den Dunnen Amalia M. Dolga |
| author_facet | Naďa Majerníková Alejandro Marmolejo-Garza Casandra Salinas Salinas Minh D. A. Luu Yuequ Zhang Marina Trombetta-Lima Tamara Tomin Ruth Birner-Gruenberger Šárka Lehtonen Jari Koistinaho Justina C. Wolters Scott Ayton Wilfred F. A. den Dunnen Amalia M. Dolga |
| author_sort | Naďa Majerníková |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b3a270feb1264fceb2a93bf047d1b14d |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-b3a270feb1264fceb2a93bf047d1b14d2025-08-20T02:18:28ZengNature Publishing GroupCell Death and Disease2041-48892024-10-01151011510.1038/s41419-024-07152-0The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progressionNaďa Majerníková0Alejandro Marmolejo-Garza1Casandra Salinas Salinas2Minh D. A. Luu3Yuequ Zhang4Marina Trombetta-Lima5Tamara Tomin6Ruth Birner-Gruenberger7Šárka Lehtonen8Jari Koistinaho9Justina C. Wolters10Scott Ayton11Wilfred F. A. den Dunnen12Amalia M. Dolga13Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenInstitute of Chemical Technologies and Analytics, Faculty of Technical Chemistry, Technische Universität WienInstitute of Chemical Technologies and Analytics, Faculty of Technical Chemistry, Technische Universität WienA. I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandNeuroscience Center, HiLIFE, University of HelsinkiLaboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, Faculty of Medical Sciences, University of Groningen, University Medical Center GroningenThe Florey Neuroscience Institute, The University of MelbourneDepartment of Pathology and Medical Biology, Research Institute Brain and Cognition, Molecular Neuroscience and Aging Research, Research School of Behavioural and Cognitive Neuroscience, University Medical Centre Groningen, University of GroningenDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Research School of Behavioural and Cognitive Neuroscience, University of GroningenAbstract 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.https://doi.org/10.1038/s41419-024-07152-0 |
| spellingShingle | Naďa Majerníková Alejandro Marmolejo-Garza Casandra Salinas Salinas Minh D. A. Luu Yuequ Zhang Marina Trombetta-Lima Tamara Tomin Ruth Birner-Gruenberger Šárka Lehtonen Jari Koistinaho Justina C. Wolters Scott Ayton Wilfred F. A. den Dunnen Amalia M. Dolga The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression Cell Death and Disease |
| title | The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression |
| title_full | The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression |
| title_fullStr | The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression |
| title_full_unstemmed | The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression |
| title_short | The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression |
| title_sort | link between amyloid β and ferroptosis pathway in alzheimer s disease progression |
| url | https://doi.org/10.1038/s41419-024-07152-0 |
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