{"doi":"10.1007/s00401-024-02835-6","title":"Elevated expression of the retrotransposon LINE-1 drives Alzheimer’s disease-associated microglial dysfunction","abstract":"Aberrant activity of the retrotransposable element long interspersed nuclear element-1 (LINE-1) has been hypothesized to contribute to cellular dysfunction in age-related disorders, including late-onset Alzheimer's disease (LOAD). However, whether LINE-1 is differentially expressed in cell types of the LOAD brain, and whether these changes contribute to disease pathology is largely unknown. Here, we examined patterns of LINE-1 expression across neurons, astrocytes, oligodendrocytes, and microglia in human postmortem prefrontal cortex tissue from LOAD patients and cognitively normal, age-matched controls. We report elevated immunoreactivity of the open reading frame 1 protein (ORF1p) encoded by LINE-1 in microglia from LOAD patients and find that this immunoreactivity correlates positively with disease-associated microglial morphology. In human iPSC-derived microglia (iMG), we found that CRISPR-mediated transcriptional activation of LINE-1 drives changes in microglial morphology and cytokine secretion and impairs the phagocytosis of amyloid beta (Aβ). We also find LINE-1 upregulation in iMG induces transcriptomic changes genes associated with antigen presentation and lipid metabolism as well as impacting the expression of many AD-relevant genes. Our data posit that heightened LINE-1 expression may trigger microglial dysregulation in LOAD and that these changes may contribute to disease pathogenesis, suggesting a central role for LINE-1 activity in human LOAD.","journal":"Acta Neuropathologica","year":2024,"id":422066,"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":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":427188,"name":"Imdadul Haq","orcid":null,"position":1,"is_corresponding":false},{"id":1216360,"name":"Jason C. Ngo","orcid":null,"position":2,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":3,"is_corresponding":false},{"id":7425,"name":"Andrew F. Teich","orcid":"0000-0002-1916-8490","position":4,"is_corresponding":false},{"id":771,"name":"Philip L. De Jager","orcid":"0000-0002-8057-2505","position":5,"is_corresponding":false},{"id":7416,"name":"Marta Olah","orcid":"0000-0003-4945-855X","position":6,"is_corresponding":false},{"id":1215650,"name":"Falak Sher","orcid":"0000-0002-4429-0084","position":7,"is_corresponding":false},{"id":1215649,"name":"Nainika Roy","orcid":"0000-0002-6903-4714","position":0,"is_corresponding":true}],"reference_count":136,"raw_metadata":null,"created_at":"2026-07-19T01:57:46.393290Z","pmid":"39604588","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":[]}