{"doi":"10.1002/alz.70474","title":"U1‐70K and U1A and tau pathogenesis in demented and non‐demented individuals with Down syndrome","abstract":"INTRODUCTION: Splicing protein mislocalization is associated with tau pathogenesis, but its role in Down syndrome (DS) is under-investigated. METHODS: Spliceosome associations with tau and plaque pathology were examined in frontal cortex from DS with dementia (DSD+) and without dementia (DSD-) using quantitative immunoblotting and immunohistochemistry. RESULTS: U1-70K and U1A levels were downregulated, and hnRNPA2B1, 3Rtau, and 4Rtau were upregulated, whereas SRSF2 and CLK1 were unchanged in DSD+. The number of U1-70K lightly labeled cells was only greater in layer III in DSD+. U1A intensely stained nuclei decreased significantly in layer III in DSD+, whereas those lightly labeled significantly increased in layers III and V-VI in DSD+. U1 mislocalization and tangles appeared in each laminae examined in both DS groups but were significantly greater in DSD+. Mislocalized U1s that co-localized with AT8, and not TauC3, were significantly increased in DSD+. DISCUSSION: U1 splicing proteins play a key role in tau pathogenesis in individuals with DS. HIGHLIGHTS: U1 mislocalization and tangle-like profiles appeared in frontal cortex layer III and V-VI neurons in Down syndrome (DS). Frontal cortex hnRNPA2B1 nuclear morphometric values decreased in layer III in DS with dementia. Frontal cortex SRSF2 and CLK1 nuclear proteins were unchanged in DSD+ and without dementia (DSD-).","journal":"Alzheimer s & Dementia","year":2025,"id":526442,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9375,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1387602,"name":"Jennifer C. Miguel","orcid":"0000-0001-5745-2241","position":1,"is_corresponding":false},{"id":350201,"name":"Muhammad Nadeem","orcid":"0000-0002-7066-4334","position":2,"is_corresponding":false},{"id":350202,"name":"Michael Malek‐Ahmadi","orcid":"0000-0001-9901-3650","position":3,"is_corresponding":false},{"id":301302,"name":"Chadwick M. Hales","orcid":"0000-0002-8757-7325","position":4,"is_corresponding":false},{"id":270466,"name":"Elizabeth Head","orcid":"0000-0003-1115-6396","position":5,"is_corresponding":false},{"id":272203,"name":"Elliott J. Mufson","orcid":"0000-0003-4438-7334","position":6,"is_corresponding":false},{"id":350200,"name":"Sylvia E. Perez","orcid":"0009-0009-1412-5721","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:50:30.402772Z","pmid":"40762109","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":[]}