iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss
© 2023 The Authors. GLIA published by Wiley Periodicals LLC..
Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:72 |
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| Enthalten in: |
Glia - 72(2024), 2 vom: 15. Feb., Seite 452-469 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Penney, Jay [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.12.2023 Date Revised 02.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/glia.24485 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss |
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| 520 | |a © 2023 The Authors. GLIA published by Wiley Periodicals LLC. | ||
| 520 | |a Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a induced pluripotent stem cells | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a microglia | |
| 650 | 4 | |a neurodegeneration | |
| 650 | 4 | |a triggering receptor expressed on myeloid cells 2 (TREM2) | |
| 650 | 7 | |a TREM2 protein, human |2 NLM | |
| 650 | 7 | |a Membrane Glycoproteins |2 NLM | |
| 650 | 7 | |a Receptors, Immunologic |2 NLM | |
| 700 | 1 | |a Ralvenius, William T |e verfasserin |4 aut | |
| 700 | 1 | |a Loon, Anjanet |e verfasserin |4 aut | |
| 700 | 1 | |a Cerit, Oyku |e verfasserin |4 aut | |
| 700 | 1 | |a Dileep, Vishnu |e verfasserin |4 aut | |
| 700 | 1 | |a Milo, Blerta |e verfasserin |4 aut | |
| 700 | 1 | |a Pao, Ping-Chieh |e verfasserin |4 aut | |
| 700 | 1 | |a Woolf, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Li-Huei |e verfasserin |4 aut | |
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