Home > Publications Database > Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency. > print

001     163471
005     20240302115205.0
024 7 _ |a 10.15252/embj.2021109108
|2 doi
024 7 _ |a pmid:35019161
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024 7 _ |a pmc:PMC8844989
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024 7 _ |a 0261-4189
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024 7 _ |a 1460-2075
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024 7 _ |a altmetric:120731924
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037 _ _ |a DZNE-2022-00231
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Reifschneider, Anika
|0 P:(DE-2719)2812094
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245 _ _ |a Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency.
260 _ _ |a Hoboken, NJ [u.a.]
|c 2022
|b Wiley
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a JOURNAL_ARTICLE
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336 7 _ |a Journal Article
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500 _ _ |a (CC BY-NC-ND)
520 _ _ |a 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.
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650 _ 7 |a frontotemporal lobar degeneration
|2 Other
650 _ 7 |a lysosomes
|2 Other
650 _ 7 |a microglia
|2 Other
650 _ 7 |a neurodegeneration
|2 Other
650 _ 7 |a progranulin
|2 Other
650 _ 7 |a Antibodies
|2 NLM Chemicals
650 _ 7 |a Grn protein, mouse
|2 NLM Chemicals
650 _ 7 |a Membrane Glycoproteins
|2 NLM Chemicals
650 _ 7 |a Progranulins
|2 NLM Chemicals
650 _ 7 |a Receptors, Immunologic
|2 NLM Chemicals
650 _ 7 |a TREM2 protein, human
|2 NLM Chemicals
650 _ 7 |a Trem2 protein, mouse
|2 NLM Chemicals
650 _ 7 |a SYK protein, human
|0 EC 2.7.10.2
|2 NLM Chemicals
650 _ 7 |a Syk Kinase
|0 EC 2.7.10.2
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Antibodies: immunology
|2 MeSH
650 _ 2 |a Antibodies: pharmacology
|2 MeSH
650 _ 2 |a Brain: diagnostic imaging
|2 MeSH
650 _ 2 |a Brain: physiopathology
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: metabolism
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: pathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Lysosomes: metabolism
|2 MeSH
650 _ 2 |a Lysosomes: pathology
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Membrane Glycoproteins: genetics
|2 MeSH
650 _ 2 |a Membrane Glycoproteins: immunology
|2 MeSH
650 _ 2 |a Membrane Glycoproteins: metabolism
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Microglia: drug effects
|2 MeSH
650 _ 2 |a Microglia: physiology
|2 MeSH
650 _ 2 |a Monocytes: drug effects
|2 MeSH
650 _ 2 |a Monocytes: metabolism
|2 MeSH
650 _ 2 |a Progranulins: deficiency
|2 MeSH
650 _ 2 |a Receptors, Immunologic: genetics
|2 MeSH
650 _ 2 |a Receptors, Immunologic: immunology
|2 MeSH
650 _ 2 |a Receptors, Immunologic: metabolism
|2 MeSH
650 _ 2 |a Syk Kinase: metabolism
|2 MeSH
700 1 _ |a Robinson, Sophie
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700 1 _ |a van Lengerich, Bettina
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700 1 _ |a Gnoerich, Johannes
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700 1 _ |a Logan, Todd
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700 1 _ |a Heindl, Steffanie
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700 1 _ |a Riedl, Lina
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700 1 _ |a Wind, Karin
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700 1 _ |a Zatcepin, Artem
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700 1 _ |a Pesämaa, Ida
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700 1 _ |a Haberl, Sophie
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700 1 _ |a Nuscher, Brigitte
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700 1 _ |a Kleinberger, Gernot
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700 1 _ |a Klimmt, Julien
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700 1 _ |a Götzl, Julia K
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700 1 _ |a Bürger, Katharina
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700 1 _ |a Brendel, Matthias
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700 1 _ |a Levin, Johannes
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700 1 _ |a Diehl-Schmid, Janine
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700 1 _ |a Suh, Jung
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700 1 _ |a Di Paolo, Gilbert
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700 1 _ |a Lewcock, Joseph W
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700 1 _ |a Monroe, Kathryn M
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700 1 _ |a Paquet, Dominik
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700 1 _ |a Capell, Anja
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700 1 _ |a Haass, Christian
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773 _ _ |a 10.15252/embj.2021109108
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