Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency
Abstract 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 pat...
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| Autor*in: |
Reifschneider, Anika [verfasserIn] Robinson, Sophie [verfasserIn] van Lengerich, Bettina [verfasserIn] Gnörich, Johannes [verfasserIn] Logan, Todd [verfasserIn] Heindl, Steffanie [verfasserIn] Vogt, Miriam A [verfasserIn] Weidinger, Endy [verfasserIn] Riedl, Lina [verfasserIn] Wind, Karin [verfasserIn] Zatcepin, Artem [verfasserIn] Pesämaa, Ida [verfasserIn] Haberl, Sophie [verfasserIn] Nuscher, Brigitte [verfasserIn] Kleinberger, Gernot [verfasserIn] Klimmt, Julien [verfasserIn] Götzl, Julia K [verfasserIn] Liesz, Arthur [verfasserIn] Bürger, Katharina [verfasserIn] Brendel, Matthias [verfasserIn] Levin, Johannes [verfasserIn] Diehl‐Schmid, Janine [verfasserIn] Suh, Jung [verfasserIn] Di Paolo, Gilbert [verfasserIn] Lewcock, Joseph W [verfasserIn] Monroe, Kathryn M [verfasserIn] Paquet, Dominik [verfasserIn] Capell, Anja [verfasserIn] Haass, Christian [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2022 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 41(2022), 4 vom: 12. Jan. |
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| Übergeordnetes Werk: |
volume:41 ; year:2022 ; number:4 ; day:12 ; month:01 |
| Links: |
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| DOI / URN: |
10.15252/embj.2021109108 |
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| Katalog-ID: |
SPR058111565 |
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| 100 | 1 | |a Reifschneider, Anika |e verfasserin |0 (orcid)0000-0001-9598-9373 |4 aut | |
| 245 | 1 | 0 | |a Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
| 264 | 1 | |c 2022 | |
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| 520 | |a Abstract 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. | ||
| 520 | |a SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. | ||
| 520 | |a Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. | ||
| 650 | 4 | |a frontotemporal lobar degeneration |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a lysosomes |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a microglia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a neurodegeneration |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a progranulin |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Robinson, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a van Lengerich, Bettina |e verfasserin |4 aut | |
| 700 | 1 | |a Gnörich, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Logan, Todd |e verfasserin |4 aut | |
| 700 | 1 | |a Heindl, Steffanie |e verfasserin |0 (orcid)0000-0003-3576-2702 |4 aut | |
| 700 | 1 | |a Vogt, Miriam A |e verfasserin |4 aut | |
| 700 | 1 | |a Weidinger, Endy |e verfasserin |4 aut | |
| 700 | 1 | |a Riedl, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Wind, Karin |e verfasserin |4 aut | |
| 700 | 1 | |a Zatcepin, Artem |e verfasserin |0 (orcid)0000-0002-0224-088X |4 aut | |
| 700 | 1 | |a Pesämaa, Ida |e verfasserin |4 aut | |
| 700 | 1 | |a Haberl, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Nuscher, Brigitte |e verfasserin |4 aut | |
| 700 | 1 | |a Kleinberger, Gernot |e verfasserin |4 aut | |
| 700 | 1 | |a Klimmt, Julien |e verfasserin |0 (orcid)0000-0003-0781-6400 |4 aut | |
| 700 | 1 | |a Götzl, Julia K |e verfasserin |4 aut | |
| 700 | 1 | |a Liesz, Arthur |e verfasserin |0 (orcid)0000-0002-9069-2594 |4 aut | |
| 700 | 1 | |a Bürger, Katharina |e verfasserin |4 aut | |
| 700 | 1 | |a Brendel, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Levin, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Diehl‐Schmid, Janine |e verfasserin |4 aut | |
| 700 | 1 | |a Suh, Jung |e verfasserin |4 aut | |
| 700 | 1 | |a Di Paolo, Gilbert |e verfasserin |0 (orcid)0000-0003-1032-1265 |4 aut | |
| 700 | 1 | |a Lewcock, Joseph W |e verfasserin |0 (orcid)0000-0003-3012-7881 |4 aut | |
| 700 | 1 | |a Monroe, Kathryn M |e verfasserin |0 (orcid)0000-0002-6901-1176 |4 aut | |
| 700 | 1 | |a Paquet, Dominik |e verfasserin |0 (orcid)0000-0003-2065-1639 |4 aut | |
| 700 | 1 | |a Capell, Anja |e verfasserin |0 (orcid)0000-0003-3118-911X |4 aut | |
| 700 | 1 | |a Haass, Christian |e verfasserin |0 (orcid)0000-0002-4869-1627 |4 aut | |
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10.15252/embj.2021109108 doi (DE-627)SPR058111565 (SPR)embj.2021109108-e DE-627 ger DE-627 rakwb eng Reifschneider, Anika verfasserin (orcid)0000-0001-9598-9373 aut Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. frontotemporal lobar degeneration (dpeaa)DE-He213 lysosomes (dpeaa)DE-He213 microglia (dpeaa)DE-He213 neurodegeneration (dpeaa)DE-He213 progranulin (dpeaa)DE-He213 Robinson, Sophie verfasserin aut van Lengerich, Bettina verfasserin aut Gnörich, Johannes verfasserin aut Logan, Todd verfasserin aut Heindl, Steffanie verfasserin (orcid)0000-0003-3576-2702 aut Vogt, Miriam A verfasserin aut Weidinger, Endy verfasserin aut Riedl, Lina verfasserin aut Wind, Karin verfasserin aut Zatcepin, Artem verfasserin (orcid)0000-0002-0224-088X aut Pesämaa, Ida verfasserin aut Haberl, Sophie verfasserin aut Nuscher, Brigitte verfasserin aut Kleinberger, Gernot verfasserin aut Klimmt, Julien verfasserin (orcid)0000-0003-0781-6400 aut Götzl, Julia K verfasserin aut Liesz, Arthur verfasserin (orcid)0000-0002-9069-2594 aut Bürger, Katharina verfasserin aut Brendel, Matthias verfasserin aut Levin, Johannes verfasserin aut Diehl‐Schmid, Janine verfasserin aut Suh, Jung verfasserin aut Di Paolo, Gilbert verfasserin (orcid)0000-0003-1032-1265 aut Lewcock, Joseph W verfasserin (orcid)0000-0003-3012-7881 aut Monroe, Kathryn M verfasserin (orcid)0000-0002-6901-1176 aut Paquet, Dominik verfasserin (orcid)0000-0003-2065-1639 aut Capell, Anja verfasserin (orcid)0000-0003-3118-911X aut Haass, Christian verfasserin (orcid)0000-0002-4869-1627 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 41(2022), 4 vom: 12. Jan. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:41 year:2022 number:4 day:12 month:01 https://dx.doi.org/10.15252/embj.2021109108 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 41 2022 4 12 01 |
| spelling |
10.15252/embj.2021109108 doi (DE-627)SPR058111565 (SPR)embj.2021109108-e DE-627 ger DE-627 rakwb eng Reifschneider, Anika verfasserin (orcid)0000-0001-9598-9373 aut Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. frontotemporal lobar degeneration (dpeaa)DE-He213 lysosomes (dpeaa)DE-He213 microglia (dpeaa)DE-He213 neurodegeneration (dpeaa)DE-He213 progranulin (dpeaa)DE-He213 Robinson, Sophie verfasserin aut van Lengerich, Bettina verfasserin aut Gnörich, Johannes verfasserin aut Logan, Todd verfasserin aut Heindl, Steffanie verfasserin (orcid)0000-0003-3576-2702 aut Vogt, Miriam A verfasserin aut Weidinger, Endy verfasserin aut Riedl, Lina verfasserin aut Wind, Karin verfasserin aut Zatcepin, Artem verfasserin (orcid)0000-0002-0224-088X aut Pesämaa, Ida verfasserin aut Haberl, Sophie verfasserin aut Nuscher, Brigitte verfasserin aut Kleinberger, Gernot verfasserin aut Klimmt, Julien verfasserin (orcid)0000-0003-0781-6400 aut Götzl, Julia K verfasserin aut Liesz, Arthur verfasserin (orcid)0000-0002-9069-2594 aut Bürger, Katharina verfasserin aut Brendel, Matthias verfasserin aut Levin, Johannes verfasserin aut Diehl‐Schmid, Janine verfasserin aut Suh, Jung verfasserin aut Di Paolo, Gilbert verfasserin (orcid)0000-0003-1032-1265 aut Lewcock, Joseph W verfasserin (orcid)0000-0003-3012-7881 aut Monroe, Kathryn M verfasserin (orcid)0000-0002-6901-1176 aut Paquet, Dominik verfasserin (orcid)0000-0003-2065-1639 aut Capell, Anja verfasserin (orcid)0000-0003-3118-911X aut Haass, Christian verfasserin (orcid)0000-0002-4869-1627 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 41(2022), 4 vom: 12. Jan. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:41 year:2022 number:4 day:12 month:01 https://dx.doi.org/10.15252/embj.2021109108 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 41 2022 4 12 01 |
| allfields_unstemmed |
10.15252/embj.2021109108 doi (DE-627)SPR058111565 (SPR)embj.2021109108-e DE-627 ger DE-627 rakwb eng Reifschneider, Anika verfasserin (orcid)0000-0001-9598-9373 aut Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. frontotemporal lobar degeneration (dpeaa)DE-He213 lysosomes (dpeaa)DE-He213 microglia (dpeaa)DE-He213 neurodegeneration (dpeaa)DE-He213 progranulin (dpeaa)DE-He213 Robinson, Sophie verfasserin aut van Lengerich, Bettina verfasserin aut Gnörich, Johannes verfasserin aut Logan, Todd verfasserin aut Heindl, Steffanie verfasserin (orcid)0000-0003-3576-2702 aut Vogt, Miriam A verfasserin aut Weidinger, Endy verfasserin aut Riedl, Lina verfasserin aut Wind, Karin verfasserin aut Zatcepin, Artem verfasserin (orcid)0000-0002-0224-088X aut Pesämaa, Ida verfasserin aut Haberl, Sophie verfasserin aut Nuscher, Brigitte verfasserin aut Kleinberger, Gernot verfasserin aut Klimmt, Julien verfasserin (orcid)0000-0003-0781-6400 aut Götzl, Julia K verfasserin aut Liesz, Arthur verfasserin (orcid)0000-0002-9069-2594 aut Bürger, Katharina verfasserin aut Brendel, Matthias verfasserin aut Levin, Johannes verfasserin aut Diehl‐Schmid, Janine verfasserin aut Suh, Jung verfasserin aut Di Paolo, Gilbert verfasserin (orcid)0000-0003-1032-1265 aut Lewcock, Joseph W verfasserin (orcid)0000-0003-3012-7881 aut Monroe, Kathryn M verfasserin (orcid)0000-0002-6901-1176 aut Paquet, Dominik verfasserin (orcid)0000-0003-2065-1639 aut Capell, Anja verfasserin (orcid)0000-0003-3118-911X aut Haass, Christian verfasserin (orcid)0000-0002-4869-1627 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 41(2022), 4 vom: 12. Jan. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:41 year:2022 number:4 day:12 month:01 https://dx.doi.org/10.15252/embj.2021109108 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 41 2022 4 12 01 |
| allfieldsGer |
10.15252/embj.2021109108 doi (DE-627)SPR058111565 (SPR)embj.2021109108-e DE-627 ger DE-627 rakwb eng Reifschneider, Anika verfasserin (orcid)0000-0001-9598-9373 aut Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. frontotemporal lobar degeneration (dpeaa)DE-He213 lysosomes (dpeaa)DE-He213 microglia (dpeaa)DE-He213 neurodegeneration (dpeaa)DE-He213 progranulin (dpeaa)DE-He213 Robinson, Sophie verfasserin aut van Lengerich, Bettina verfasserin aut Gnörich, Johannes verfasserin aut Logan, Todd verfasserin aut Heindl, Steffanie verfasserin (orcid)0000-0003-3576-2702 aut Vogt, Miriam A verfasserin aut Weidinger, Endy verfasserin aut Riedl, Lina verfasserin aut Wind, Karin verfasserin aut Zatcepin, Artem verfasserin (orcid)0000-0002-0224-088X aut Pesämaa, Ida verfasserin aut Haberl, Sophie verfasserin aut Nuscher, Brigitte verfasserin aut Kleinberger, Gernot verfasserin aut Klimmt, Julien verfasserin (orcid)0000-0003-0781-6400 aut Götzl, Julia K verfasserin aut Liesz, Arthur verfasserin (orcid)0000-0002-9069-2594 aut Bürger, Katharina verfasserin aut Brendel, Matthias verfasserin aut Levin, Johannes verfasserin aut Diehl‐Schmid, Janine verfasserin aut Suh, Jung verfasserin aut Di Paolo, Gilbert verfasserin (orcid)0000-0003-1032-1265 aut Lewcock, Joseph W verfasserin (orcid)0000-0003-3012-7881 aut Monroe, Kathryn M verfasserin (orcid)0000-0002-6901-1176 aut Paquet, Dominik verfasserin (orcid)0000-0003-2065-1639 aut Capell, Anja verfasserin (orcid)0000-0003-3118-911X aut Haass, Christian verfasserin (orcid)0000-0002-4869-1627 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 41(2022), 4 vom: 12. Jan. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:41 year:2022 number:4 day:12 month:01 https://dx.doi.org/10.15252/embj.2021109108 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 41 2022 4 12 01 |
| allfieldsSound |
10.15252/embj.2021109108 doi (DE-627)SPR058111565 (SPR)embj.2021109108-e DE-627 ger DE-627 rakwb eng Reifschneider, Anika verfasserin (orcid)0000-0001-9598-9373 aut Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. frontotemporal lobar degeneration (dpeaa)DE-He213 lysosomes (dpeaa)DE-He213 microglia (dpeaa)DE-He213 neurodegeneration (dpeaa)DE-He213 progranulin (dpeaa)DE-He213 Robinson, Sophie verfasserin aut van Lengerich, Bettina verfasserin aut Gnörich, Johannes verfasserin aut Logan, Todd verfasserin aut Heindl, Steffanie verfasserin (orcid)0000-0003-3576-2702 aut Vogt, Miriam A verfasserin aut Weidinger, Endy verfasserin aut Riedl, Lina verfasserin aut Wind, Karin verfasserin aut Zatcepin, Artem verfasserin (orcid)0000-0002-0224-088X aut Pesämaa, Ida verfasserin aut Haberl, Sophie verfasserin aut Nuscher, Brigitte verfasserin aut Kleinberger, Gernot verfasserin aut Klimmt, Julien verfasserin (orcid)0000-0003-0781-6400 aut Götzl, Julia K verfasserin aut Liesz, Arthur verfasserin (orcid)0000-0002-9069-2594 aut Bürger, Katharina verfasserin aut Brendel, Matthias verfasserin aut Levin, Johannes verfasserin aut Diehl‐Schmid, Janine verfasserin aut Suh, Jung verfasserin aut Di Paolo, Gilbert verfasserin (orcid)0000-0003-1032-1265 aut Lewcock, Joseph W verfasserin (orcid)0000-0003-3012-7881 aut Monroe, Kathryn M verfasserin (orcid)0000-0002-6901-1176 aut Paquet, Dominik verfasserin (orcid)0000-0003-2065-1639 aut Capell, Anja verfasserin (orcid)0000-0003-3118-911X aut Haass, Christian verfasserin (orcid)0000-0002-4869-1627 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 41(2022), 4 vom: 12. Jan. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:41 year:2022 number:4 day:12 month:01 https://dx.doi.org/10.15252/embj.2021109108 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 41 2022 4 12 01 |
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English |
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Enthalten in The EMBO Journal 41(2022), 4 vom: 12. Jan. volume:41 year:2022 number:4 day:12 month:01 |
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Enthalten in The EMBO Journal 41(2022), 4 vom: 12. Jan. volume:41 year:2022 number:4 day:12 month:01 |
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Article |
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frontotemporal lobar degeneration lysosomes microglia neurodegeneration progranulin |
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Reifschneider, Anika @@aut@@ Robinson, Sophie @@aut@@ van Lengerich, Bettina @@aut@@ Gnörich, Johannes @@aut@@ Logan, Todd @@aut@@ Heindl, Steffanie @@aut@@ Vogt, Miriam A @@aut@@ Weidinger, Endy @@aut@@ Riedl, Lina @@aut@@ Wind, Karin @@aut@@ Zatcepin, Artem @@aut@@ Pesämaa, Ida @@aut@@ Haberl, Sophie @@aut@@ Nuscher, Brigitte @@aut@@ Kleinberger, Gernot @@aut@@ Klimmt, Julien @@aut@@ Götzl, Julia K @@aut@@ Liesz, Arthur @@aut@@ Bürger, Katharina @@aut@@ Brendel, Matthias @@aut@@ Levin, Johannes @@aut@@ Diehl‐Schmid, Janine @@aut@@ Suh, Jung @@aut@@ Di Paolo, Gilbert @@aut@@ Lewcock, Joseph W @@aut@@ Monroe, Kathryn M @@aut@@ Paquet, Dominik @@aut@@ Capell, Anja @@aut@@ Haass, Christian @@aut@@ |
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2022-01-12T00:00:00Z |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058111565</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241026064810.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241026s2022 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.2021109108</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058111565</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.2021109108-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Reifschneider, Anika</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-9598-9373</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2022</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">frontotemporal lobar degeneration</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">lysosomes</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">microglia</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield 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Reifschneider, Anika |
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Reifschneider, Anika misc frontotemporal lobar degeneration misc lysosomes misc microglia misc neurodegeneration misc progranulin Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency frontotemporal lobar degeneration (dpeaa)DE-He213 lysosomes (dpeaa)DE-He213 microglia (dpeaa)DE-He213 neurodegeneration (dpeaa)DE-He213 progranulin (dpeaa)DE-He213 |
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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
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Reifschneider, Anika |
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Reifschneider, Anika Robinson, Sophie van Lengerich, Bettina Gnörich, Johannes Logan, Todd Heindl, Steffanie Vogt, Miriam A Weidinger, Endy Riedl, Lina Wind, Karin Zatcepin, Artem Pesämaa, Ida Haberl, Sophie Nuscher, Brigitte Kleinberger, Gernot Klimmt, Julien Götzl, Julia K Liesz, Arthur Bürger, Katharina Brendel, Matthias Levin, Johannes Diehl‐Schmid, Janine Suh, Jung Di Paolo, Gilbert Lewcock, Joseph W Monroe, Kathryn M Paquet, Dominik Capell, Anja Haass, Christian |
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Reifschneider, Anika |
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10.15252/embj.2021109108 |
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loss of trem2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
| abstract |
Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. © The Author(s) 2022 |
| abstractGer |
Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. © The Author(s) 2022 |
| abstract_unstemmed |
Abstract 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. SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages. Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD. © The Author(s) 2022 |
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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058111565</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241026064810.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241026s2022 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.2021109108</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058111565</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.2021109108-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Reifschneider, Anika</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-9598-9373</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2022</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">SYNOPSIS Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition. Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.Lysosomal dysfunction is independent of microglia activation stages.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">frontotemporal lobar degeneration</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">lysosomes</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">microglia</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield 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| score |
7.3986187 |