{"doi":"10.1073/pnas.2401420121","title":"Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration","abstract":"Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer’s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T (“ hi T”) cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hi T cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hi T mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":423038,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.945,"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":241435,"name":"Altan Rentsendorj","orcid":"0009-0001-4322-8107","position":1,"is_corresponding":false},{"id":449987,"name":"Michelle Jhun","orcid":null,"position":2,"is_corresponding":false},{"id":318854,"name":"Robert M. 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Raskatov","orcid":"0000-0002-0082-9113","position":16,"is_corresponding":false},{"id":241441,"name":"Keith L. Black","orcid":"0000-0002-0546-4934","position":17,"is_corresponding":false},{"id":1218031,"name":"Dwain K. Irvin","orcid":"0009-0008-8870-928X","position":18,"is_corresponding":false},{"id":11729,"name":"Brian A. Williams","orcid":"0000-0003-3253-611X","position":19,"is_corresponding":false},{"id":448698,"name":"Christopher J. 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