{"doi":"10.1016/j.celrep.2023.112841","title":"Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model","abstract":"The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the \"C\" or \"T\" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the \"C\" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk \"C\" allele carriers.","journal":"Cell Reports","year":2023,"id":331082,"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":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.958,"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":487671,"name":"Jianfei Chao","orcid":null,"position":1,"is_corresponding":false},{"id":274824,"name":"Cheng Wang","orcid":"0000-0002-7822-259X","position":2,"is_corresponding":false},{"id":486834,"name":"Guihua Sun","orcid":"0000-0001-7337-3543","position":3,"is_corresponding":false},{"id":474236,"name":"Daniel Roeth","orcid":null,"position":4,"is_corresponding":false},{"id":1055882,"name":"Wei Liu","orcid":"0000-0002-0123-4090","position":5,"is_corresponding":false},{"id":486832,"name":"Xianwei Chen","orcid":"0000-0002-5646-3245","position":6,"is_corresponding":false},{"id":531844,"name":"Li Li","orcid":"0000-0003-0524-7515","position":7,"is_corresponding":false},{"id":276475,"name":"Erpo Tian","orcid":null,"position":8,"is_corresponding":false},{"id":486829,"name":"Lizhao Feng","orcid":"0000-0002-9843-3941","position":9,"is_corresponding":false},{"id":231744,"name":"Hayk Davtyan","orcid":"0000-0001-8554-6456","position":10,"is_corresponding":false},{"id":7841,"name":"Mathew Blurton-Jones","orcid":"0000-0002-7770-7157","position":11,"is_corresponding":false},{"id":434048,"name":"Markus Kalkum","orcid":"0000-0002-9506-671X","position":12,"is_corresponding":false},{"id":274829,"name":"Yanhong Shi","orcid":"0000-0002-3938-5839","position":13,"is_corresponding":false},{"id":864493,"name":"Zhenqing Liu","orcid":"0000-0002-2822-2022","position":0,"is_corresponding":true}],"reference_count":121,"raw_metadata":null,"created_at":"2026-07-19T01:09:19.317824Z","pmid":"37494190","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":[]}