Natural Killer Cells Improve Cognitive Function and Support to Induce Amyloid Beta Clearance by Functional Recovery of Impaired Microglia in Natural Killer Cell‐treated Alzheimer’s Diseases Mouse Model

Abstract

AbstractBackgroundDysfunction of microglia that plays a pivotal role in amyloid beta clearance is recognized to be involved in pathological progression of the Alzheimer’s diseases. Natural killer (NK) cells participate in homeostatic immune‐modulation and immune‐surveillance by secreting immune‐boosting signaling molecules. These molecules can serve as cell‐based therapeutics for AD. In this study, we found that the activated NK cells eliminated Aβ plaques, resulting in a marked improvement in behavior in mice with AD. This improvement may be associated with the recovery in microglial function due to the upregulation of phagocytic activity and autophagy genes.MethodNK cells were isolated, using a negative selection process, from the spleens of BALB/c mice and subsequently expanded to 1×108 cells.ResultThe cultured NK cells were intravenously administered into APP/PS1 mutant mice. There was dramatic reduction of Aβ deposition in the cortex and dentate gyrus areas of the brain in these mice following the NK cell treatment. While phosphate‐buffered saline APP/PS1 control mice exhibited learning deficits in the escape platform, the NK cell‐treated mice showed reduced escape latency in the Morris water maze test. Mouse microglia, in the AD model, were isolated using CD11b positive magnetic activated cell sorting method. RNA sequencing was performed using total RNA isolated from mouse brain hippocampus tissue, to explore differential gene expression levels. Hierarchical cluster heat maps revealed the recovered gene populations in the NK‐treated microglial group. The percentage of genes upregulated in the total gene ontology groups were significantly altered in NK treated/sham ratio group (i.e., 171 upregulated immune response‐related genes). The homeostatic and disease‐associated microglia (DAM)‐related genes that were increased in microglia isolated from APP/PS1 mouse brain were downregulated after NK treatment. KEGG pathway analysis projected the autophagy signaling pathways as critical pathways associated with amyloid beta clearance. Our analysis showed that treatment of mice with NK cells recovered gene signatures involved in phagocytic activity.ConclusionThese findings show that NK cells, which are known to have low in vivo toxicity, could be a potential therapeutic option for AD that could be rapidly translated to the clinic.