%0 Journal Article
%T Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.
%A Panwar A
%A Rentsendorj A
%A Jhun M
%A Cohen RM
%A Cordner R
%A Gull N
%A Pechnick RN
%A Duvall G
%A Mardiros A
%A Golchian D
%A Schubloom H
%A Jin LW
%A Van Dam D
%A Vermeiren Y
%A De Reu H
%A De Deyn PP
%A Raskatov JA
%A Black KL
%A Irvin DK
%A Williams BA
%A Wheeler CJ
%J Proc Natl Acad Sci U S A
%V 121
%N 29
%D 2024 Jul 16
%M 38995966
%F 12.779
%R 10.1073/pnas.2401420121
%X 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.