A microglia clonal inflammatory disorder in Alzheimer’s disease
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones...
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eLife Sciences Publications Ltd
2025-03-01
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| Online Access: | https://elifesciences.org/articles/96519 |
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| author | Rocio Vicario Stamatina Fragkogianni Leslie Weber Tomi Lazarov Yang Hu Samantha Y Hayashi Barbara Craddock Nicholas D Socci Araitz Alberdi Ann Baako Oyku Ay Masato Ogishi Estibaliz Lopez-Rodrigo Rajya Kappagantula Agnes Viale Christine A Iacobuzio-Donahue Ting Zhou Richard M Ransohoff Richard Chesworth Netherlands Brain Bank Omar Abdel-Wahab Bertrand Boisson Olivier Elemento Jean-Laurent Casanova W Todd Miller Frédéric Geissmann |
| author_facet | Rocio Vicario Stamatina Fragkogianni Leslie Weber Tomi Lazarov Yang Hu Samantha Y Hayashi Barbara Craddock Nicholas D Socci Araitz Alberdi Ann Baako Oyku Ay Masato Ogishi Estibaliz Lopez-Rodrigo Rajya Kappagantula Agnes Viale Christine A Iacobuzio-Donahue Ting Zhou Richard M Ransohoff Richard Chesworth Netherlands Brain Bank Omar Abdel-Wahab Bertrand Boisson Olivier Elemento Jean-Laurent Casanova W Todd Miller Frédéric Geissmann |
| author_sort | Rocio Vicario |
| collection | DOAJ |
| description | Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients. |
| format | Article |
| id | doaj-art-b7b9309b8c854c5ba616612ffa5b7fe4 |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-b7b9309b8c854c5ba616612ffa5b7fe42025-08-20T02:57:04ZengeLife Sciences Publications LtdeLife2050-084X2025-03-011310.7554/eLife.96519A microglia clonal inflammatory disorder in Alzheimer’s diseaseRocio Vicario0https://orcid.org/0000-0002-7894-5261Stamatina Fragkogianni1Leslie Weber2Tomi Lazarov3https://orcid.org/0000-0002-6312-0080Yang Hu4Samantha Y Hayashi5Barbara Craddock6Nicholas D Socci7Araitz Alberdi8Ann Baako9Oyku Ay10Masato Ogishi11Estibaliz Lopez-Rodrigo12Rajya Kappagantula13Agnes Viale14Christine A Iacobuzio-Donahue15Ting Zhou16Richard M Ransohoff17https://orcid.org/0000-0003-0175-6910Richard Chesworth18Netherlands Brain Bank19Omar Abdel-Wahab20https://orcid.org/0000-0002-3907-6171Bertrand Boisson21Olivier Elemento22Jean-Laurent Casanova23W Todd Miller24Frédéric Geissmann25https://orcid.org/0000-0001-5029-2468Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesDepartment of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell New York, New York, United StatesDepartment of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, New York, United StatesDepartment of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, New York, United StatesMarie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesHuman Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesMarie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesHuman Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesSKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesThird Rock Ventures, Boston, United StatesThird Rock Ventures, Boston, United StatesNetherlands Brain Bank, Amsterdam, NetherlandsHuman Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United StatesDepartment of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell New York, New York, United StatesSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United StatesDepartment of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, New York, United StatesImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United StatesSomatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.https://elifesciences.org/articles/96519somatic mutationsAlzheimer's diseasemicrogliamap kinase |
| spellingShingle | Rocio Vicario Stamatina Fragkogianni Leslie Weber Tomi Lazarov Yang Hu Samantha Y Hayashi Barbara Craddock Nicholas D Socci Araitz Alberdi Ann Baako Oyku Ay Masato Ogishi Estibaliz Lopez-Rodrigo Rajya Kappagantula Agnes Viale Christine A Iacobuzio-Donahue Ting Zhou Richard M Ransohoff Richard Chesworth Netherlands Brain Bank Omar Abdel-Wahab Bertrand Boisson Olivier Elemento Jean-Laurent Casanova W Todd Miller Frédéric Geissmann A microglia clonal inflammatory disorder in Alzheimer’s disease eLife somatic mutations Alzheimer's disease microglia map kinase |
| title | A microglia clonal inflammatory disorder in Alzheimer’s disease |
| title_full | A microglia clonal inflammatory disorder in Alzheimer’s disease |
| title_fullStr | A microglia clonal inflammatory disorder in Alzheimer’s disease |
| title_full_unstemmed | A microglia clonal inflammatory disorder in Alzheimer’s disease |
| title_short | A microglia clonal inflammatory disorder in Alzheimer’s disease |
| title_sort | microglia clonal inflammatory disorder in alzheimer s disease |
| topic | somatic mutations Alzheimer's disease microglia map kinase |
| url | https://elifesciences.org/articles/96519 |
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