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Published July 16, 2024 | Version Published
Journal Article Open

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

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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 (“hiT”) cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hiT 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.

Copyright and License

© 2024 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

Acknowledgement

We gratefully acknowledge the patients and families who provided tissue and blood for analysis; the Cedars-Sinai Research Institute Biobehavioral Core for conducting mouse behavioral tests; Dr. Igor Antoshechkin for RNAseq performance; Dr. Jeremy Sanders and Dr. Sol Katzman for guidance in gene expression analysis; Ms. Hannah Schubloom and Mia Oviatt for excellent administrative support and editing; and Dr. Kristina Trujillo for editing and proofreading. NIH Grant (UC Davis Alzheimer’s Disease Center) P30AG10129 (L.-W.J.); NIH Grant R21NSO54162 (C.J.W.); NIH Grant R21AG033394 (R.M.C.); Cedars-Sinai Medical Center Biobehavioral Core (R.N.P.); Joseph Drown Foundation (C.J.W.); Maxine Dunitz Neurosurgical Institute (C.J.W.); and Maxine Dunitz Neurosurgical Institute (D.K.I.).

Contributions

R.C., R.N.P., J.A.R., D.K.I., B.A.W., and C.J.W. designed research; A.P., A.R., M.J., R.M.C., R.C., N.G., R.N.P., G.D., A.M., D.G., L.-W.J., D.V.D., Y.V., H.D.R., P.P.D.D., D.K.I., B.A.W., and C.J.W. performed research; A.R., R.C., R.N.P., L.-W.J., Y.V., H.D.R., P.P.D.D., K.L.B., D.K.I., B.A.W., and C.J.W. contributed new reagents/analytic tools; A.P., A.R., M.J., R.M.C., R.C., N.G., R.N.P., G.D., A.M., H.S., D.V.D., Y.V., H.D.R., P.P.D.D., D.K.I., B.A.W., and C.J.W. analyzed data; R.N.P., L.-W.J., and P.P.D.D. advised on paper framing & design; J.A.R. facilitated collaborations, advised on paper framing & design; K.L.B. and C.J.W. facilitated collaborations, supervised facilities and personnel; and A.P., A.R., R.C., and C.J.W. wrote the paper.

Data Availability

RNAseq, Western blot quantitation, behavioral test data, flow cytometry data have been deposited in Open Science Framework (https://doi.org/10.17605/OSF.IO/354JS) (62). Model Organisms and/or the means to generate them will be made generally available for research (non-commercial) use.

Conflict of Interest

C.J.W. is the author of patents PCT/US2016/049598, WO2017/040594, and PCT/US2019/017879. R.C. and K.L.B. are co-authors on patent PCT/US2019/017879. PCT/US2016/049598 and WO 2017/040594 are licensed by Cedars-Sinai Medical Center to T-Neuro Pharma, Inc. C.J.W. has received salary and ownership interest in T-Neuro Pharma, Inc.

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Additional details

Identifiers

ISSN
1091-6490

Related works

Is new version of
Discussion Paper: 10.1101/2024.01.22.576704 (DOI)
Discussion Paper: PMC10849535 (PMCID)

Funding

National Institutes of Health
P30AG10129
National Institutes of Health
R21NSO54162
National Institutes of Health
R21AG033394
Cedars-Sinai Medical Center
Joseph Drown Foundation