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 var...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-10-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-020-00409-0 |
| _version_ | 1818192380352790528 |
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| author | Vaishnavi S. Jadhav Peter B. C. Lin Taylor Pennington Gonzalo Viana Di Prisco Asha Jacob Jannu Guixiang Xu Miguel Moutinho Jie Zhang Brady K. Atwood Shweta S. Puntambekar Stephanie J. Bissel Adrian L. Oblak Gary E. Landreth Bruce T. Lamb |
| author_facet | Vaishnavi S. Jadhav Peter B. C. Lin Taylor Pennington Gonzalo Viana Di Prisco Asha Jacob Jannu Guixiang Xu Miguel Moutinho Jie Zhang Brady K. Atwood Shweta S. Puntambekar Stephanie J. Bissel Adrian L. Oblak Gary E. Landreth Bruce T. Lamb |
| author_sort | Vaishnavi S. Jadhav |
| collection | DOAJ |
| description | 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. Trem2 Y38C/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. Trem2 Y38C/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. |
| first_indexed | 2024-12-12T00:29:35Z |
| format | Article |
| id | doaj.art-5b13dac21794463aaf99674ad8572591 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-12T00:29:35Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-5b13dac21794463aaf99674ad85725912022-12-22T00:44:32ZengBMCMolecular Neurodegeneration1750-13262020-10-0115111610.1186/s13024-020-00409-0Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult miceVaishnavi S. Jadhav0Peter B. C. Lin1Taylor Pennington2Gonzalo Viana Di Prisco3Asha Jacob Jannu4Guixiang Xu5Miguel Moutinho6Jie Zhang7Brady K. Atwood8Shweta S. Puntambekar9Stephanie J. Bissel10Adrian L. Oblak11Gary E. Landreth12Bruce T. Lamb13Paul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicineDepartment of Medicine, Indiana University School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicineDepartment of Medical and Molecular Genetics, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicinePaul and Carole Stark Neurosciences Research Institute, Indiana University, School of MedicineAbstract 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. Trem2 Y38C/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. Trem2 Y38C/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.http://link.springer.com/article/10.1186/s13024-020-00409-0NHDTrem2-Y38CEarly-onset dementiaTranscriptomicsOligodendrocytes/myelinSynaptic loss |
| spellingShingle | Vaishnavi S. Jadhav Peter B. C. Lin Taylor Pennington Gonzalo Viana Di Prisco Asha Jacob Jannu Guixiang Xu Miguel Moutinho Jie Zhang Brady K. Atwood Shweta S. Puntambekar Stephanie J. Bissel Adrian L. Oblak Gary E. Landreth Bruce T. Lamb Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice Molecular Neurodegeneration NHD Trem2-Y38C Early-onset dementia Transcriptomics Oligodendrocytes/myelin Synaptic loss |
| title | Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
| title_full | Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
| title_fullStr | Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
| title_full_unstemmed | Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
| title_short | Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice |
| title_sort | trem2 y38c mutation and loss of trem2 impairs neuronal synapses in adult mice |
| topic | NHD Trem2-Y38C Early-onset dementia Transcriptomics Oligodendrocytes/myelin Synaptic loss |
| url | http://link.springer.com/article/10.1186/s13024-020-00409-0 |
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