Age-related memory CD8 T cells induce and track Alzheimers-like neurodegeneration

Panwar, A.; Rentsendorj, A.; Jhun, M.; Cohen, R. M.; Cordner, R.; Gull, N.; Pechnick, R. N.; Duvall, G.; Mardiros, A.; Golchian, D.; Schubloom, H.; Jin, L.-W.; Van Dam, D.; Vermeiren, Y.; De Reu, H.; De Deyn, P. P.; Raskatov, J. A.; Black, K. L.; Irvin, D. K.; Williams, B. A.; Wheeler, C. J.

doi:10.1101/2024.01.22.576704

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bioRxiv · 10.1101/2024.01.22.576704

Age-related memory CD8 T cells induce and track Alzheimers-like neurodegeneration

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Abstract

Cerebral (A{beta}) plaque and (pTau) tangle deposition are hallmarks of Alzheimers disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of A{beta}/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{beta}/fibrillar pTau, however, appears to vary depending on the animal model used. Our prior work suggested that antigen-specific memory CD8 T ("hiT") cells act upstream of A{beta}/pTau after brain injury. Here we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of A{beta}/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 IFN{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, a promising AD biomarker candidate. Our work is the first to identify an age-related factor acting upstream of A{beta}/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD. Significance StatementThis study changes our view of Alzheimers Disease (AD) initiation and progression. Mutations promoting cerebral beta-amyloid (A{beta}) deposition guarantee rare genetic forms of AD. Thus, the prevailing hypothesis has been that A{beta} is central to initiation and progression of all AD, despite contrary animal and patient evidence. We show that age-related T cells generate neurodegeneration with compelling features of AD in mice, with distinct T cell functions required for pathological initiation and neurodegenerative progression. Knowledge from these mice was applied to successfully predict previously unknown features of human AD and generate novel tools for its clinical management.

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Panwar, A., Rentsendorj, A., Jhun, M., Cohen, R. M., Cordner, R., Gull, N., Pechnick, R. N., Duvall, G., Mardiros, A., Golchian, D., Schubloom, H., Jin, L.-W., Van Dam, D., Vermeiren, Y., De Reu, H., De Deyn, P. P., Raskatov, J. A., Black, K. L., Irvin, D. K., Williams, B. A., Wheeler, C. J.. 2024-01-22. Age-related memory CD8 T cells induce and track Alzheimers-like neurodegeneration. https://doi.org/10.1101/2024.01.22.576704

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