A microglia clonal inflammatory disorder in Alzheimer's Disease.

Autor:	Vicario R; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Fragkogianni S; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Weber L; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Lazarov T; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Hu Y; Department of Physiology and Biophysics, Institute for Computational Biomedicine,Weill Cornell New York, NY 10021, USA., Hayashi SY; Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661., Craddock BP; Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661., Socci ND; Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Alberdi A; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Baako A; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Ay O; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Ogishi M; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA., Lopez-Rodrigo E; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Kappagantula R; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Viale A; Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Iacobuzio-Donahue CA; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Zhou T; SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Ransohoff RM; Third Rock Ventures, Boston MA, USA., Chesworth R; Third Rock Ventures, Boston MA, USA., Abdel-Wahab O; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA., Boisson B; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA., Elemento O; Department of Physiology and Biophysics, Institute for Computational Biomedicine,Weill Cornell New York, NY 10021, USA., Casanova JL; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA., Miller WT; Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8661., Geissmann F; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 03. Date of Electronic Publication: 2024 Aug 03.
DOI:	10.1101/2024.01.25.577216
Abstrakt:	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 human, 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. Competing Interests: Competing interests. FG has been a paid consultant (no equity) to Third Rock Ventures from 2018 to 2020. Sequencing costs and analysis in this study were covered in part by a SRA between Third Rock venture and MSKCC. This work led to patents PCT/US2022/037893/WO2023004054A1 ‘Methods and compositions for the treatment of alzheimer’s disease’ by MSKCC and PCT/US2018/047964 ‘Kinase mutation-associated neurodegenerative disorders by MSKCC’.
Databáze:	MEDLINE
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