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

Akanksha Panwar, Altan Rentsendorj, Michelle Jhun, Robert Cohen, Ryan Cordner, Nicole Gull, Robert Pechnick, Gretchen Duvall, Armen Mardiros, David Golchian, Hannah Schubloom, Lee-Way Jin, Debby Van Dam, Y.P.Y. Vermeiren, Hans de Reu, Peter Paul De Deyn, Jevgenij Raskatov, Keith Black, Dwain Irvin, Brian WilliamsChristopher Wheeler*

*Corresponding author for this work

Research output: Working paperPreprint

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/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 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. Our work is the first to 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.
Original languageEnglish
PublisherBioRxiv
DOIs
Publication statusPublished - Jan 2024

Fingerprint

Dive into the research topics of 'Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration'. Together they form a unique fingerprint.

Cite this