{"doi":"10.1093/jnen/nlae137","title":"Cytoplasmic expression of trans-active response DNA-binding protein-43 in aged mice display hippocampal sclerosis-like degeneration and neuronal loss with reduced lifespan","abstract":"Trans-active response DNA-binding protein-43 (TDP-43) is the major pathological protein in motor neuron disease and TDP-43 pathology has been described in the brains of up to 50% of patients with Alzheimer disease (AD). Hippocampal sclerosis of aging (HS-A), an age-related neuropathology characterized by severe neuronal loss and gliosis in CA1 and/or subiculum, is found in ∼80% of cases that are positive for phosphorylated TDP-43. HS-A is seen as a co-pathology in cases with AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), and frontotemporal degeneration. To understand the pathogenetic relationships between HS-A and LATE-NC, mice that selectively express human TDP-43 and TDP-43 with a defective nuclear localization signal (ΔNLS) in the hippocampus, alone or in an APP/PSEN1 background, were evaluated using histology, HALO software's object recognition algorithms, and protein expression assays. Twenty-four-month-old mice expressing cytosolic TDP-43 displayed marked neuronal loss and atrophy in the hippocampus, decreased β-amyloid plaque deposition and modulation of microglia and intermediate filament activation. TDP-43ΔNLS-expressing mice survived to only ∼24 months of age whether or not they had an APP/PSEN1 background. This HS-A-like model may provide insights into the pathogenesis of neurodegeneration seen in HS-A and in other TDP-43 proteinopathies.","journal":"Journal of Neuropathology & Experimental Neurology","year":2025,"id":551366,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"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":1342617,"name":"Matthew B Dopler","orcid":"0000-0002-9708-8090","position":1,"is_corresponding":false},{"id":1257165,"name":"Sanaz Arezoumandan","orcid":"0000-0001-6569-9009","position":2,"is_corresponding":false},{"id":1447514,"name":"Damian Osei‐KanKam","orcid":null,"position":3,"is_corresponding":false},{"id":1447515,"name":"Stephani A. Davis","orcid":null,"position":4,"is_corresponding":false},{"id":455452,"name":"Kaouther Ajroud","orcid":"0000-0002-2891-1186","position":5,"is_corresponding":false},{"id":455451,"name":"Jaclyn Lilek","orcid":"0000-0002-7085-8331","position":6,"is_corresponding":false},{"id":1447516,"name":"Eva Bambakadis","orcid":null,"position":7,"is_corresponding":false},{"id":1447153,"name":"Raymond M. Shapiro","orcid":"0000-0002-6865-3097","position":8,"is_corresponding":false},{"id":651396,"name":"Margaret E. Flanagan","orcid":"0000-0002-8360-2618","position":9,"is_corresponding":false},{"id":232093,"name":"Nigel J. Cairns","orcid":"0000-0001-9858-3344","position":10,"is_corresponding":false},{"id":1044467,"name":"Michael A. Gitcho","orcid":"0000-0002-9223-5426","position":11,"is_corresponding":false},{"id":768213,"name":"Ashley Anderson","orcid":"0000-0002-4744-7614","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:54:25.065895Z","pmid":"39864404","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":[]}