دورية أكاديمية
Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency.
| العنوان: | Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency. |
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| المؤلفون: | Reifschneider, Anika, Robinson, Sophie, Zatcepin, Artem, Pesämaa, Ida, Haberl, Sophie, Nuscher, Brigitte, Kleinberger, Gernot, Klimmt, Julien, Götzl, Julia K, Liesz, Arthur, Bürger, Katharina, Brendel, Matthias, van Lengerich, Bettina, Levin, Johannes, Diehl-Schmid, Janine, Suh, Jung, Di Paolo, Gilbert, Lewcock, Joseph W, Monroe, Kathryn M, Paquet, Dominik, Capell, Anja, Haass, Christian, Gnoerich, Johannes, Logan, Todd, Heindl, Steffanie, Vogt, Miriam A, Weidinger, Endy, Riedl, Lina, Wind, Karin |
| المصدر: | The EMBO journal 41(4), e109108 (2022). doi:10.15252/embj.2021109108 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | info:eu-repo/classification/ddc/570, Animals, Antibodies: immunology, Antibodies: pharmacology, Brain: diagnostic imaging, Brain: physiopathology, Disease Models, Animal, Female, Frontotemporal Lobar Degeneration: metabolism, Frontotemporal Lobar Degeneration: pathology, Humans, Lysosomes: metabolism, Lysosomes: pathology, Male, Membrane Glycoproteins: genetics, Membrane Glycoproteins: immunology, Membrane Glycoproteins: metabolism, Mice, Inbred C57BL, Knockout, Microglia: drug effects, Microglia: physiology, Monocytes: drug effects, Monocytes: metabolism, Progranulins: deficiency, Receptors, Immunologic: genetics, Immunologic: immunology, Immunologic: metabolism |
| جغرافية الموضوع: | DE |
| الوصف: | Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/issn/1460-2075; info:eu-repo/semantics/altIdentifier/issn/0261-4189; info:eu-repo/semantics/altIdentifier/pmid/pmid:35019161; https://pub.dzne.de/record/163471Test; https://pub.dzne.de/search?p=id:%22DZNE-2022-00231%22Test |
| الإتاحة: | https://doi.org/10.15252/embj.2021109108Test https://pub.dzne.de/record/163471Test https://pub.dzne.de/search?p=id:%22DZNE-2022-00231%22Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.A87A5DB1 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |