Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H...
Ausführliche Beschreibung
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| Autor*in: |
Jadhav, Vaishnavi S. [verfasserIn] Lin, Peter B. C. [verfasserIn] Pennington, Taylor [verfasserIn] Di Prisco, Gonzalo Viana [verfasserIn] Jannu, Asha Jacob [verfasserIn] Xu, Guixiang [verfasserIn] Moutinho, Miguel [verfasserIn] Zhang, Jie [verfasserIn] Atwood, Brady K. [verfasserIn] Puntambekar, Shweta S. [verfasserIn] Bissel, Stephanie J. [verfasserIn] Oblak, Adrian L. [verfasserIn] Landreth, Gary E. [verfasserIn] Lamb, Bruce T. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Molecular neurodegeneration - London : Biomed Central, 2006, 15(2020), 1 vom: 28. Okt. |
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| Übergeordnetes Werk: |
volume:15 ; year:2020 ; number:1 ; day:28 ; month:10 |
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| DOI / URN: |
10.1186/s13024-020-00409-0 |
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| Katalog-ID: |
SPR041653300 |
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| 245 | 1 | 0 | |a Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
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| 520 | |a Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. | ||
| 650 | 4 | |a NHD |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a -Y38C |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Early-onset dementia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Transcriptomics |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Oligodendrocytes/myelin |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Synaptic loss |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Synaptic plasticity |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Lin, Peter B. C. |e verfasserin |4 aut | |
| 700 | 1 | |a Pennington, Taylor |e verfasserin |4 aut | |
| 700 | 1 | |a Di Prisco, Gonzalo Viana |e verfasserin |4 aut | |
| 700 | 1 | |a Jannu, Asha Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Guixiang |e verfasserin |4 aut | |
| 700 | 1 | |a Moutinho, Miguel |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Atwood, Brady K. |e verfasserin |4 aut | |
| 700 | 1 | |a Puntambekar, Shweta S. |e verfasserin |4 aut | |
| 700 | 1 | |a Bissel, Stephanie J. |e verfasserin |4 aut | |
| 700 | 1 | |a Oblak, Adrian L. |e verfasserin |4 aut | |
| 700 | 1 | |a Landreth, Gary E. |e verfasserin |4 aut | |
| 700 | 1 | |a Lamb, Bruce T. |e verfasserin |4 aut | |
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10.1186/s13024-020-00409-0 doi (DE-627)SPR041653300 (SPR)s13024-020-00409-0-e DE-627 ger DE-627 rakwb eng 570 ASE Jadhav, Vaishnavi S. verfasserin aut Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. NHD (dpeaa)DE-He213 -Y38C (dpeaa)DE-He213 Early-onset dementia (dpeaa)DE-He213 Transcriptomics (dpeaa)DE-He213 Oligodendrocytes/myelin (dpeaa)DE-He213 Synaptic loss (dpeaa)DE-He213 Synaptic plasticity (dpeaa)DE-He213 Lin, Peter B. C. verfasserin aut Pennington, Taylor verfasserin aut Di Prisco, Gonzalo Viana verfasserin aut Jannu, Asha Jacob verfasserin aut Xu, Guixiang verfasserin aut Moutinho, Miguel verfasserin aut Zhang, Jie verfasserin aut Atwood, Brady K. verfasserin aut Puntambekar, Shweta S. verfasserin aut Bissel, Stephanie J. verfasserin aut Oblak, Adrian L. verfasserin aut Landreth, Gary E. verfasserin aut Lamb, Bruce T. verfasserin aut Enthalten in Molecular neurodegeneration London : Biomed Central, 2006 15(2020), 1 vom: 28. Okt. (DE-627)515978361 (DE-600)2244557-2 1750-1326 nnns volume:15 year:2020 number:1 day:28 month:10 https://dx.doi.org/10.1186/s13024-020-00409-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2020 1 28 10 |
| spelling |
10.1186/s13024-020-00409-0 doi (DE-627)SPR041653300 (SPR)s13024-020-00409-0-e DE-627 ger DE-627 rakwb eng 570 ASE Jadhav, Vaishnavi S. verfasserin aut Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. NHD (dpeaa)DE-He213 -Y38C (dpeaa)DE-He213 Early-onset dementia (dpeaa)DE-He213 Transcriptomics (dpeaa)DE-He213 Oligodendrocytes/myelin (dpeaa)DE-He213 Synaptic loss (dpeaa)DE-He213 Synaptic plasticity (dpeaa)DE-He213 Lin, Peter B. C. verfasserin aut Pennington, Taylor verfasserin aut Di Prisco, Gonzalo Viana verfasserin aut Jannu, Asha Jacob verfasserin aut Xu, Guixiang verfasserin aut Moutinho, Miguel verfasserin aut Zhang, Jie verfasserin aut Atwood, Brady K. verfasserin aut Puntambekar, Shweta S. verfasserin aut Bissel, Stephanie J. verfasserin aut Oblak, Adrian L. verfasserin aut Landreth, Gary E. verfasserin aut Lamb, Bruce T. verfasserin aut Enthalten in Molecular neurodegeneration London : Biomed Central, 2006 15(2020), 1 vom: 28. Okt. (DE-627)515978361 (DE-600)2244557-2 1750-1326 nnns volume:15 year:2020 number:1 day:28 month:10 https://dx.doi.org/10.1186/s13024-020-00409-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2020 1 28 10 |
| allfields_unstemmed |
10.1186/s13024-020-00409-0 doi (DE-627)SPR041653300 (SPR)s13024-020-00409-0-e DE-627 ger DE-627 rakwb eng 570 ASE Jadhav, Vaishnavi S. verfasserin aut Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. NHD (dpeaa)DE-He213 -Y38C (dpeaa)DE-He213 Early-onset dementia (dpeaa)DE-He213 Transcriptomics (dpeaa)DE-He213 Oligodendrocytes/myelin (dpeaa)DE-He213 Synaptic loss (dpeaa)DE-He213 Synaptic plasticity (dpeaa)DE-He213 Lin, Peter B. C. verfasserin aut Pennington, Taylor verfasserin aut Di Prisco, Gonzalo Viana verfasserin aut Jannu, Asha Jacob verfasserin aut Xu, Guixiang verfasserin aut Moutinho, Miguel verfasserin aut Zhang, Jie verfasserin aut Atwood, Brady K. verfasserin aut Puntambekar, Shweta S. verfasserin aut Bissel, Stephanie J. verfasserin aut Oblak, Adrian L. verfasserin aut Landreth, Gary E. verfasserin aut Lamb, Bruce T. verfasserin aut Enthalten in Molecular neurodegeneration London : Biomed Central, 2006 15(2020), 1 vom: 28. Okt. (DE-627)515978361 (DE-600)2244557-2 1750-1326 nnns volume:15 year:2020 number:1 day:28 month:10 https://dx.doi.org/10.1186/s13024-020-00409-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2020 1 28 10 |
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10.1186/s13024-020-00409-0 doi (DE-627)SPR041653300 (SPR)s13024-020-00409-0-e DE-627 ger DE-627 rakwb eng 570 ASE Jadhav, Vaishnavi S. verfasserin aut Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. NHD (dpeaa)DE-He213 -Y38C (dpeaa)DE-He213 Early-onset dementia (dpeaa)DE-He213 Transcriptomics (dpeaa)DE-He213 Oligodendrocytes/myelin (dpeaa)DE-He213 Synaptic loss (dpeaa)DE-He213 Synaptic plasticity (dpeaa)DE-He213 Lin, Peter B. C. verfasserin aut Pennington, Taylor verfasserin aut Di Prisco, Gonzalo Viana verfasserin aut Jannu, Asha Jacob verfasserin aut Xu, Guixiang verfasserin aut Moutinho, Miguel verfasserin aut Zhang, Jie verfasserin aut Atwood, Brady K. verfasserin aut Puntambekar, Shweta S. verfasserin aut Bissel, Stephanie J. verfasserin aut Oblak, Adrian L. verfasserin aut Landreth, Gary E. verfasserin aut Lamb, Bruce T. verfasserin aut Enthalten in Molecular neurodegeneration London : Biomed Central, 2006 15(2020), 1 vom: 28. Okt. (DE-627)515978361 (DE-600)2244557-2 1750-1326 nnns volume:15 year:2020 number:1 day:28 month:10 https://dx.doi.org/10.1186/s13024-020-00409-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2020 1 28 10 |
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10.1186/s13024-020-00409-0 doi (DE-627)SPR041653300 (SPR)s13024-020-00409-0-e DE-627 ger DE-627 rakwb eng 570 ASE Jadhav, Vaishnavi S. verfasserin aut Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. NHD (dpeaa)DE-He213 -Y38C (dpeaa)DE-He213 Early-onset dementia (dpeaa)DE-He213 Transcriptomics (dpeaa)DE-He213 Oligodendrocytes/myelin (dpeaa)DE-He213 Synaptic loss (dpeaa)DE-He213 Synaptic plasticity (dpeaa)DE-He213 Lin, Peter B. C. verfasserin aut Pennington, Taylor verfasserin aut Di Prisco, Gonzalo Viana verfasserin aut Jannu, Asha Jacob verfasserin aut Xu, Guixiang verfasserin aut Moutinho, Miguel verfasserin aut Zhang, Jie verfasserin aut Atwood, Brady K. verfasserin aut Puntambekar, Shweta S. verfasserin aut Bissel, Stephanie J. verfasserin aut Oblak, Adrian L. verfasserin aut Landreth, Gary E. verfasserin aut Lamb, Bruce T. verfasserin aut Enthalten in Molecular neurodegeneration London : Biomed Central, 2006 15(2020), 1 vom: 28. Okt. (DE-627)515978361 (DE-600)2244557-2 1750-1326 nnns volume:15 year:2020 number:1 day:28 month:10 https://dx.doi.org/10.1186/s13024-020-00409-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2020 1 28 10 |
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Enthalten in Molecular neurodegeneration 15(2020), 1 vom: 28. Okt. volume:15 year:2020 number:1 day:28 month:10 |
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NHD -Y38C Early-onset dementia Transcriptomics Oligodendrocytes/myelin Synaptic loss Synaptic plasticity |
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Jadhav, Vaishnavi S. @@aut@@ Lin, Peter B. C. @@aut@@ Pennington, Taylor @@aut@@ Di Prisco, Gonzalo Viana @@aut@@ Jannu, Asha Jacob @@aut@@ Xu, Guixiang @@aut@@ Moutinho, Miguel @@aut@@ Zhang, Jie @@aut@@ Atwood, Brady K. @@aut@@ Puntambekar, Shweta S. @@aut@@ Bissel, Stephanie J. @@aut@@ Oblak, Adrian L. @@aut@@ Landreth, Gary E. @@aut@@ Lamb, Bruce T. @@aut@@ |
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Jadhav, Vaishnavi S. Lin, Peter B. C. Pennington, Taylor Di Prisco, Gonzalo Viana Jannu, Asha Jacob Xu, Guixiang Moutinho, Miguel Zhang, Jie Atwood, Brady K. Puntambekar, Shweta S. Bissel, Stephanie J. Oblak, Adrian L. Landreth, Gary E. Lamb, Bruce T. |
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trem2 y38c mutation and loss of trem2 impairs neuronal synapses in adult mice |
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Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
| abstract |
Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. |
| abstractGer |
Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. |
| abstract_unstemmed |
Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. |
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Lin, Peter B. C. Pennington, Taylor Di Prisco, Gonzalo Viana Jannu, Asha Jacob Xu, Guixiang Moutinho, Miguel Zhang, Jie Atwood, Brady K. Puntambekar, Shweta S. Bissel, Stephanie J. Oblak, Adrian L. Landreth, Gary E. Lamb, Bruce T. |
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| score |
7.3985558 |