{Reference Type}: Journal Article
{Title}: Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.
{Author}: Panwar A;Rentsendorj A;Jhun M;Cohen RM;Cordner R;Gull N;Pechnick RN;Duvall G;Mardiros A;Golchian D;Schubloom H;Jin LW;Van Dam D;Vermeiren Y;De Reu H;De Deyn PP;Raskatov JA;Black KL;Irvin DK;Williams BA;Wheeler CJ;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 121
{Issue}: 29
{Year}: 2024 Jul 16
{Factor}: 12.779
{DOI}: 10.1073/pnas.2401420121
{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.