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

Autor: Penney J; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Biomedical Sciences, AVC, University of Prince Edward Island, Charlottetown, PE, Canada., Ralvenius WT; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Loon A; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Cerit O; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Dileep V; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Milo B; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Pao PC; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Woolf H; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Tsai LH; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Glia [Glia] 2024 Feb; Vol. 72 (2), pp. 452-469. Date of Electronic Publication: 2023 Nov 15.
DOI: 10.1002/glia.24485
Abstrakt: 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.
(© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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