{"doi":"10.1016/j.ajpath.2011.07.001","title":"Ablation of TNF-RI/RII Expression in Alzheimer's Disease Mice Leads to an Unexpected Enhancement of Pathology","abstract":null,"journal":"The American Journal of Pathology","year":2011,"id":612154,"datarank":4.253382413469748,"base_score":4.59511985013459,"endowment":4.59511985013459,"self_citation_contribution":0.6892679775201885,"citation_network_contribution":3.56411443594956,"self_endowment_contribution":0.6892679775201885,"citer_contribution":3.56411443594956,"corpus_percentile":null,"corpus_rank":null,"citation_count":98,"citer_count":97,"citers_with_citation_signal":90,"citers_with_endowment":90,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":287447,"name":"Michael A. Mastrangelo","orcid":null,"position":1,"is_corresponding":false},{"id":1576023,"name":"Diala Habib","orcid":null,"position":2,"is_corresponding":false},{"id":1576024,"name":"Wade C. Narrow","orcid":null,"position":3,"is_corresponding":false},{"id":1074582,"name":"Sara A. Knowlden","orcid":"0000-0001-7483-2967","position":4,"is_corresponding":false},{"id":1094019,"name":"Terry W. Wright","orcid":"0000-0001-6531-2214","position":5,"is_corresponding":false},{"id":1181720,"name":"William J. Bowers","orcid":"0000-0003-2255-2116","position":6,"is_corresponding":false},{"id":1576022,"name":"Sara L. Montgomery","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Ablation of TNF-RI/RII Expression in Alzheimer's Disease Mice Leads to an Unexpected Enhancement of Pathology","abstract":"Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-α, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-α is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-α signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-α receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-α receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-α. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-β phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-β peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD.","is_dataset_classified":null,"base_score":4.59511985013459,"endowment":4.59511985013459,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21835156","pmcid":"PMC3181376","openalex_id":"https://openalex.org/W10297594","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"F31-AG038063","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01-AG023593","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01-AG026328","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG023593","title":null},{"funder_name":"NIA NIH HHS","grant_id":"F31 AG038063","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG026328","title":null}],"total_grants":6,"fwci":3.694,"citation_percentile":0.93155867,"influential_citations":0,"citation_trend":[{"year":2012,"count":5},{"year":2013,"count":8},{"year":2014,"count":10},{"year":2015,"count":10},{"year":2016,"count":6},{"year":2017,"count":10},{"year":2018,"count":7},{"year":2019,"count":6},{"year":2020,"count":9},{"year":2021,"count":13},{"year":2022,"count":5},{"year":2023,"count":7},{"year":2024,"count":2}],"oa_status":"bronze","license":"http://www.elsevier.com/open-access/userlicense/1.0/","oa_locations":[{"url":"http://ajp.amjpathol.org/article/S0002944011006377/pdf","host_type":"journal"},{"url":"http://ajp.amjpathol.org/article/S0002944011006377/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0002944011006377?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0002944011006377?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.ajpath.2011.07.001","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/21835156","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3181376","host_type":"repository"}],"fields_of_study":["Alzheimer's disease research and treatments","Neuroinflammation and Neurodegeneration Mechanisms","Immune Response and Inflammation","Adaptor Proteins, Signal Transducing","Aging","Alzheimer Disease","Amyloid","Amyloid beta-Protein Precursor","Animals","Brain","CA1 Region, Hippocampal","CA3 Region, Hippocampal","Calcium-Binding Proteins","Crosses, Genetic","Female","Humans","Lipopolysaccharide Receptors","Long-Term Potentiation","Male","Mice","Mice, Knockout","Microfilament Proteins","Microglia","Phagocytosis","Receptors, Tumor Necrosis Factor, Type I","Receptors, Tumor Necrosis Factor, Type II","Synapses","Transgenes","Tumor Necrosis Factor-alpha","tau Proteins"],"mesh_terms":["Aging","Alzheimer Disease","Amyloid","Animals","Brain","Calcium-Binding Proteins","Crosses, Genetic","Female","Humans","Male","Microfilament Proteins","Phagocytosis","Synapses","Tumor Necrosis Factor-alpha","Amyloid beta-Protein Precursor","tau Proteins","Microglia","Long-Term Potentiation","Mice, Knockout","Lipopolysaccharide Receptors","Transgenes","Receptors, Tumor Necrosis Factor, Type I","Receptors, Tumor Necrosis Factor, Type II","Adaptor Proteins, Signal Transducing","Mice","CA1 Region, Hippocampal","CA3 Region, Hippocampal"],"keywords":["Neuroinflammation","Microglia","Tumor necrosis factor alpha","Pathogenesis","Cytokine","Receptor","Alzheimer's disease","Biology","Genetically modified mouse","Immunology","Neuroscience","Inflammation","Medicine","Transgene","Pathology","Internal medicine","Disease","Genetics","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T01:51:42.897696Z","pmid":null,"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":[]}