Antigen- specific age- related memory CD8 T cells induce and track Alzheimer's- like neurodegeneration

• 成果类型: Article
• 署名作者: Panwar, Akanksha; Rentsendorj, Altan; Jhun, Michelle; Cohen, Robert M.; Cordner, Ryan; Gull, Nicole; Pechnick, Robert N.; Duvall, Gretchen; Mardiros, Armen; Golchian, David; Schubloom, Hannah; Jin, Lee - Way; Van Dam, Debby; Vermeiren, Yannick; De Reu, Hans; Deyn, Peter Paul De; Raskatov, Jevgenij A.; Black, Keith L.; Irvin, Dwain K.; Williams, Brian A.; Wheeler, Christopher J.
• 署名单位: Cedars Sinai Medical Center; Emory University; Emory University; Cedars Sinai Medical Center; Western University of Health Sciences; University of California System; University of California Davis; University of Antwerp; University of Groningen; University of Groningen; University of Groningen; University of Antwerp; Wageningen University & Research; University of Antwerp; University of California System; University of California Santa Cruz; California Institute of Technology; Brigham Young University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11356
• DOI: 10.1073/pnas.2401420121
• 发表日期: 2024-07-16
• 关键词: mild cognitive impairment; amyloid-beta-protein; mouse model; transgenic mice; tau pathology; disease; plaques; brain; proliferation; performance

摘要

Cerebral (Af3) f3 ) 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 Af3/pTau f3 /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 Af3/pTau, f3 /pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-- specific memory CD8 T (hiT) hi T) cells act upstream of Af3/pTau f3 /pTau after brain injury. Here, we examine whether hiT T cells influence sporadic AD- like pathophysiology upstream of Af3/pTau. f3 /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 IFN gamma gamma 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,- 217, a promising AD biomarker candidate. We identify an age-- related factor acting upstream of Af3/pTau f3 /pTau to initiate AD- like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.