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iPSC ‐derived microglia carrying the TREM2 R47H /+ mutation are proinflammatory and promote synapse loss
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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“Notably, iPSC-derived microglia with altered expression of the sAD risk genes APOE4 and TREM2 display pronounced phenotypic differences from control microglia, such as impaired phagocytosis, whereas mutations involved in familial AD have a more limited impact on microglial function [51, 60–63, 119–122].”
From microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer’s disease patients (2026) · cites this paper as [122]
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Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · cited 3×
“TREM2 has been shown to play a role in developmental synaptic pruning in the mouse brain, and microglia have been reported to engage in inappropriate synaptic pruning in adult AD model mice (Filipello et al., 2018; Hong et al., 2016; Salter & Stevens, 2017).”
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Yang, G., Xu, X., Gao, W., Wang, X., Zhao, Y., & Xu, Y. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1700692 · Cited by 85
Microglia, Trem2, and Neurodegeneration
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Microglial phagocytosis in Alzheimer disease
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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
- Cited by
- 52
- References
- 38
- Language
- en
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