Uncovering the cytophenotypic and transcriptomic features of natural killer cells derived from peripheral blood of patients with Alzheimer's disease

Background Alzheimer's disease (AD) has been recognized as the most common neurodegenerative disease. Despite immunodysregulation being involved in AD pathogenesis, the systematic and detailed dissection of the cellular and transcriptomic characteristics of natural killer cells (NKs) in peripheral blood of AD patients is largely obscure. Objective To investigate the cytophenotypic and transcriptomic features of NKs in peripheral blood of AD patients. Methods We used flow cytometry assay, co-culturing, RNA-SEQ, multifaceted bioinformatics analyses (e.g., GSEA, GO, KEGG, PCA), and ELISA and qRT-PCR analysis for the comparison of the cytophenotypic and transcriptomic signatures of heathy donors-NKs (HD-NKs) and AD-NKs. Results Compared with HD-NKs, AD-NKs showed increase in the content of NKs in peripheral blood mononuclear cells (PBMCs). After a 14-day ex vivo expansion and activation, the content of AD-NKs also revealed a significant increase. Expanded AD-NKs exhibited higher cellular viability and cytotoxicity than HD-NKs. Both HD-NKs and AD-NKs revealed conservations in gene expression profiling and genetic variations, yet with multifaceted variations in diverse gene sets and the concomitant biological processes (e.g., nerve structural organization, negative regulation of immune, Wnt signaling pathway, cytotoxicity against tumor cell lines). Compared to HD-NKs, AD-NKs revealed abnormally high levels of neuroinflammation-related gene expression and cytokine secretion. Conclusions Collectively, our data indicated the similarities and variations between HD-NKs and AD-NKs both at the cellular and transcriptomic levels, which would supply new references for further dissecting the pathogenesis of AD from the aspect of NKs and benefiting the development of novel therapeutic regimens in the future.