{"doi":"10.1002/glia.24485","title":"<scp>iPSC</scp>‐derived microglia carrying the <scp>TREM2 R47H</scp>/+ 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.","journal":"Glia","year":2023,"id":322301,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":74601,"name":"William T. Ralvenius","orcid":"0000-0002-0408-3443","position":1,"is_corresponding":false},{"id":17048,"name":"Anjanet Loon","orcid":null,"position":2,"is_corresponding":false},{"id":40704,"name":"Oyku Cerit","orcid":"0000-0002-3957-7689","position":3,"is_corresponding":false},{"id":16445,"name":"Vishnu Dileep","orcid":"0000-0001-9181-2191","position":4,"is_corresponding":false},{"id":84820,"name":"Blerta Milo","orcid":null,"position":5,"is_corresponding":false},{"id":11598,"name":"Ping-Chieh Pao","orcid":"0000-0001-6788-7185","position":6,"is_corresponding":false},{"id":1035840,"name":"Hannah Woolf","orcid":"0009-0004-8509-388X","position":7,"is_corresponding":false},{"id":11618,"name":"Li-Huei Tsai","orcid":"0000-0003-1262-0592","position":8,"is_corresponding":false},{"id":315774,"name":"Jay Penney","orcid":null,"position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:07:42.497873Z","pmid":"37969043","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}