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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,16]]},"abstract":"<jats:p>\n                    Cerebral (A\u03b2) plaque and (pTau) tangle deposition are hallmarks of Alzheimer\u2019s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of A\u03b2\/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 A\u03b2\/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T (\u201c\n                    <jats:sup>hi<\/jats:sup>\n                    T\u201d) cells act upstream of A\u03b2\/pTau after brain injury. Here, we examine whether\n                    <jats:sup>hi<\/jats:sup>\n                    T cells influence sporadic AD-like pathophysiology upstream of A\u03b2\/pTau. Examining neuropathology, gene expression, and behavior in our\n                    <jats:sup>hi<\/jats:sup>\n                    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 IFN\u03b3 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 A\u03b2\/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2401420121","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T13:40:04Z","timestamp":1720791604000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["Antigen-specific age-related memory CD8 T cells induce and track Alzheimer\u2019s-like neurodegeneration"],"prefix":"10.1073","volume":"121","author":[{"given":"Akanksha","family":"Panwar","sequence":"first","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4322-8107","authenticated-orcid":false,"given":"Altan","family":"Rentsendorj","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Jhun","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department Psychiatry &amp; Behavioral Sciences and Neuroscience Program, Graduate Division of Biological and Biomedical Sciences (GDBBS), Emory University, Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Cordner","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"},{"name":"Department Biomedical &amp; Translational Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1956-5648","authenticated-orcid":false,"given":"Nicole","family":"Gull","sequence":"additional","affiliation":[{"name":"Department Biomedical &amp; Translational Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N.","family":"Pechnick","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific Western University of Health Sciences, Pomona, CA 91766"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen","family":"Duvall","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armen","family":"Mardiros","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Golchian","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Schubloom","sequence":"additional","affiliation":[{"name":"Department Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee-Way","family":"Jin","sequence":"additional","affiliation":[{"name":"Department Medical Pathology and Laboratory Medicine, Laboratory Medicine, Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) 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