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iPSC ‐derived microglia carrying the TREM2 R47H /+ mutation are proinflammatory and promote synapse loss

Penney, Jay, Ralvenius, William T., Loon, Anjanet, Cerit, Oyku, Dileep, Vishnu, Milo, Blerta, Pao, Ping‐Chieh, Woolf, Hannah, Tsai, Li‐Huei·2024·Glia
DOI 10.1002/glia.24485
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Abstract

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.

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Figures

Figure 1 The TREM2 R47H/+ mutation alters microglial gene expression and induces a proinflammatory signature.
Figure 1 The TREM2 R47H/+ mutation alters microglial gene expression and induces a proinflammatory signature.CC-BY-NC · From the PDF
Image 2
CC-BY-NC · From the PDF
Figure 3 The TREM2 R47H/+ mutation impairs microglial uptake of brain-relevant substrates. (A) Images of TREM2 R47H/+ and isogenic control microglia stained for IBA1 (red) and SVP38 (green) following 3 hours uptake of mouse synaptosomes. A no-synaptosome condition using control cells is included to verify SVP38 specificity. Scale bar = 10 μm. (B) Images of TREM2 R47H/+ and control microglia stained for IBA1 (red) and MBP (green) following 3 hours uptake of mouse myelin. A no myelin condition using control cells is included to verify MBP specificity. Scale bar = 10 μm. (C) Images of TREM2 R47H/+ and control microglia stained for IBA1 (red) following 3 hours uptake of A β 42 -488 (green). A no-A β 42 -488 condition using control cells is included to verify signal specificity. Scale bar = 10 μm. (D) Quantification of pHrodo-synaptosome signal in flow cytometry experiments using TREM2 R47H/+ and control microglia. n=6 for CTRL-A, CTRL-B, R47H-A and R47H-B. *p<0.05. Student's t-test. (E) Quantification of pHrodo-myelin signal in flow cytometry experiments using TREM2 R47H/+ and control microglia. n=7 for CTRL-A, CTRL-B, R47H-A and R47H-B. ***p<0.001. Student's t-test. (F) Quantification of A β 42 -488 signal in flow cytometry experiments using TREM2 R47H/+ and control microglia. n=6 for CTRL-A, CTRL-B, R47H-A and R47H-B. ***p<0.001. Student's t-test.
Figure 3 The TREM2 R47H/+ mutation impairs microglial uptake of brain-relevant substrates. (A) Images of TREM2 R47H/+ and isogenic control microglia stained for IBA1 (red) and SVP38 (green) following 3 hours uptake of mouse synaptosomes. A no-synaptosome condition using control cells is included to verify SVP38 specificity. Scale bar = 10 μm. (B) Images of TREM2 R47H/+ and control microglia stained for IBA1 (red) and MBP (green) following 3 hours uptake of mouse myelin. A no myelin condition using control cells is included to verify MBP specificity. Scale bar = 10 μm. (C) Images of TREM2 R47H/+ and control microglia stained for IBA1 (red) following 3 hours uptake of A β 42 -488 (green). A no-A β 42 -488 condition using control cells is included to verify signal specificity. Scale bar = 10 μm. (D) Quantification of pHrodo-synaptosome signal in flow cytometry experiments using TREM2 R47H/+ and control microglia. n=6 for CTRL-A, CTRL-B, R47H-A and R47H-B. *p<0.05. Student's t-test. (E) Quantification of pHrodo-myelin signal in flow cytometry experiments using TREM2 R47H/+ and control microglia. n=7 for CTRL-A, CTRL-B, R47H-A and R47H-B. ***p<0.001. Student's t-test. (F) Quantification of A β 42 -488 signal in flow cytometry experiments using TREM2 R47H/+ and control microglia. n=6 for CTRL-A, CTRL-B, R47H-A and R47H-B. ***p<0.001. Student's t-test.CC-BY-NC · From the PDF
Figure 4 TREM2 R47H/+ microglia show an impaired response following injury in an in vitro model.
Figure 4 TREM2 R47H/+ microglia show an impaired response following injury in an in vitro model.CC-BY-NC · From the PDF
Figure 5 Transplanted TREM2 R47H/+ microglia reduce synapse density in the mouse brain. (A) Tile-scan image of representative hippocampus following xenotransplant using control iPSC-microglia, stained with DAPI (blue), the neuronal marker β -Tubulin 3 (TUJ1, red), the microglia marker IBA1 (green) and the human nuclei-specific marker STEM101 (white). Scale bar = 100 μm, inset scale bar = 10 μm. (B) Images of transplanted control and R47H/+ microglia in hippocampal area CA1, stained for DAPI (blue), IBA1 (green) STEM101 (red). Scale bar = 50 μm. (C) Quantification of the number of STEM101 positive cells in brain sections from mice transplanted with control and TREM2 R47H/+ microglia. n=6 for CTRL-A, 5 for CTRL-B, 5 for R47H-A, 4 for R47H-B. (D) Images of DAPI (blue) and MBP (red) in hippocampi from mice transplanted with PBS or control or TREM2 R47H/+ microglia. Scale bar = 50 μm. (E) Images of DAPI (blue) and SVP38 (green) in hippocampi
Figure 5 Transplanted TREM2 R47H/+ microglia reduce synapse density in the mouse brain. (A) Tile-scan image of representative hippocampus following xenotransplant using control iPSC-microglia, stained with DAPI (blue), the neuronal marker β -Tubulin 3 (TUJ1, red), the microglia marker IBA1 (green) and the human nuclei-specific marker STEM101 (white). Scale bar = 100 μm, inset scale bar = 10 μm. (B) Images of transplanted control and R47H/+ microglia in hippocampal area CA1, stained for DAPI (blue), IBA1 (green) STEM101 (red). Scale bar = 50 μm. (C) Quantification of the number of STEM101 positive cells in brain sections from mice transplanted with control and TREM2 R47H/+ microglia. n=6 for CTRL-A, 5 for CTRL-B, 5 for R47H-A, 4 for R47H-B. (D) Images of DAPI (blue) and MBP (red) in hippocampi from mice transplanted with PBS or control or TREM2 R47H/+ microglia. Scale bar = 50 μm. (E) Images of DAPI (blue) and SVP38 (green) in hippocampiCC-BY-NC · From the PDF

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Citations

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Metadata

Authors
Penney, J., Ralvenius, W. T., Loon, A., Cerit, O., Dileep, V., Milo, B., Pao, P., Woolf, H., & Tsai, L.
Affiliations
Picower Institute for Learning and Memory, Massachusetts Institute of Technology Cambridge Massachusetts USA
ORCID
Penney, Jay
Venue
Glia
Publisher
Wiley
Published
2023-11-15
Volume
72
Issue
2
Pages
452-469
ISSN
  • 0894-1491
  • 1098-1136
DOI
10.1002/glia.24485
Cited by
52
References
38
Language
en
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor)

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