{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Penney J"],"funding":["NIA NIH HHS"],"pagination":["452-469"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10904109"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["72(2)"],"pubmed_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."],"journal":["Glia"],"pubmed_title":["iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss."],"pmcid":["PMC10904109"],"funding_grant_id":["RF1 AG054321","RF1 AG062377"],"pubmed_authors":["Loon A","Ralvenius WT","Penney J","Dileep V","Cerit O","Pao PC","Tsai LH","Milo B","Woolf H"],"additional_accession":[]},"is_claimable":false,"name":"iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2026-06-02T11:59:08.793Z","creation":"2025-04-03T23:22:34.803Z"},"accession":"S-EPMC10904109","cross_references":{"pubmed":["37969043"],"doi":["10.1002/glia.24485"]}}