Single cell sequencing reveals important immune cell features in an Alzheimer’s disease model

Authors

• S Rajhans
• E Mondell
• J Madigan
• N Truongvo
• L Wang
• M Kelly
• SM Sadowski
• HE Arda

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Amyloid beta plaques and neurofibrillary tau tangles in the brain result in neurodegeneration and cognitive decline. Microglia, brain-resident macrophages, play a major role in AD progression, but the role of non-microglial immune cells are least understood. In our study, we used a mouse model (5xFAD) with human mutations in the Amyloid Precursor Protein and Presenilin genes to mimic AD pathology. Using high-dimensional flow cytometry, single-cell RNA-seq, and single-cell T-cell receptor-seq (scTCR-seq), we studied innate and adaptive immune cells in neurodegeneration. Our results showed increased alpha-beta T cells in the 5xFAD brains compared to the wild-type B6 (WT) brains at 4 and 12 months of age. Unsupervised clustering revealed a Type I Interferon responsive CD8+ T cells subset, termed disease associated CD8+ T cells (DATs), significantly enriched in 5xFAD brains. scTCR-seq analysis identified unique TCR clonotypes enriched in 5xFAD brains, with one leading clonotype indicating mucosa-associated invariant T cells (MAITs). The TCR alpha CDR3 region of this clonotype was conserved across human and mouse. Further analysis of other TCR repertoire datasets from mouse tauopathy model and cerebrospinal fluid from AD patients confirmed the MAIT cell enrichment in AD. Recent studies have linked MAITs to cognitive function and blood brain barrier integrity. Therefore, understanding the precise role of MAITs and DATs is crucial. In conclusion, our findings suggest the involvement of DATs and MAITs in AD progression. Characterizing their tissue resident location and functions may guide the development of AD therapies.

Scientific Focus Area: Immunology

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