Peripherally activated brain CD8+ T cells promote AD in mice with Alzheimer’s Disease

Authors

• TA Christensen
• JW Hoskins
• DR Eiser
• E Char
• M Mobaraki
• I Collins
• LT Amundadottir

Abstract

Alzheimer’s Disease (AD) is neurodegenerative disease linked to accumulation of Aβ plaques, neurofibrillary tangles, and chronic neuroinflammation. Although the role of the adaptive immunity in AD remains poorly understood, recent findings indicate that CD8+ T cells increase in the AD brain. Our aim was to characterize CD8+ T-cells and to investigate if they are required in AD progression. We immunized female 5xFAD mice at pre- (2-3 months) and post-onset of AD (7-8 months) with an Aβ-CoreS RNA vaccine encoding A1-11 on the surface of HBsAg particles. The CD8+ T cells were quantified from the brain of these mice and unvaccinated 5xFAD mice using immunofluorescence (IF) staining (n=4-7). We further characterized the activation state of brain CD8+ T cells from saline perfused 5xFAD mice using flow cytometry (n = 8-11). Similarly, stained humans tissued with AD (79-90 years old) were quantified for CD8+ T-cells. Our results reveal that compared to WT, AD significantly increases brain CD8+ T cells exhibiting cytotoxic but exhausted phenotype. These affects were significantly increased in vaccinated mice, linking the increase of brain CD8+ T cells to the exacerbation of AD. The brain CD8+ T cells positively correlated with cognitive decline and Aβ plaque accumulation with their activation induced in the periphery. To do this, they likely target microglia, as in both mice and humans with AD we detected significantly more brain CD8+ T cells tightly attached to activated microglia than in non-AD groups. Overall, our results indicate that brain CD8+ T cells play pathogenic role in AD.

Scientific Focus Area: Immunology

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