ALZHEIMERS RESEARCH PROJECT: Role of CD8 T cell in the pathogenesis of Alzheimer's disease

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, with inflammation increasingly recognized as a key contributing factor. Recent studies have identified highly differentiated and clonally expanded CD8+ T cells in the brains and cerebrospinal fluid (CSF) of both AD patients and mouse models. However, the role of CD8+ T cells in AD remains inconsistent across different models and methodologies. To address this, we conducted a parallel investigation using two widely studied AD mouse models: 5xFAD and APP/PS1. By crossbreeding each with CD8 knockout (CD8KO) strains, we assessed behavioral changes in the absence of CD8+ T cells. In the 5xFAD strain, CD8 deficiency led to altered nighttime activity without affecting working memory, while the APP/PS1 strain showed no significant changes in either parameter. These results suggest strain-specific differences in the contribution of CD8+ T cells to AD pathology. We then performed single-cell RNA and TCR sequencing (scRNA-seq and scTCR-seq) on brain and CSF samples from both models. This revealed an increase in effector memory CD8+ T cells in the brain, an enrichment of effector CD8+ T cells in the CSF, and the presence of clonally expanded TCR sequences-some shared across models, others unique to each strain. In parallel, we applied liquid chromatography–mass spectrometry (LC-MS) to brain tissue and identified candidate MHC class I epitopes unique to AD mice. Currently, we are validating TCR–antigen interactions in vitro and quantifying amyloid plaque accumulation in the hippocampus of both AD models lacking CD8+ T cells.