Adoptive NK cell transfer confers neuroprotection by attenuating neuroinflammation and alpha-synuclein pathology in a mouse model of synucleionpathy

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Abstract Background Natural killer (NK) cells are key effector lymphoid cells involved in both innate and adaptive immunity and are capable of clearing abnormally aggregated α-synuclein (aSyn). In preclinical Parkinson’s disease (PD) models, NK cell depletion worsens motor deficits and increases insoluble aSyn accumulation, suggesting a neuroprotective role. However, the therapeutic potential of NK cell transfer in modulating aSyn pathology and neurodegeneration remains unexplored. Methods To assess the efficacy of NK cell therapy, we administered biweekly systemic injection of untouched NK cells isolated from B6C3H donor mice into 2-month-old pre symptomatic homozygous M83 transgenic mice injected human aSyn preformed fibrils (PFFs). Neurological function was assessed via clasping behavior and clinical scoring. aSyn pathology and dopaminergic neurodegeneration were evaluated via immunohistochemistry. CyTOF-based immune profiling and multiplex ELISA were performed to characterize central and peripheral immune responses. Results Adoptive NK cell therapy improved motor function and reduced aSyn pathology in a region- and dose-dependent manner, with significant reductions in phosphorylated-aSyn (p-aSyn) and TH + neuronal loss in the substantia nigra. NK cell treatment modulated the CNS immune landscape by reducing CD11b + CD45 high and MHCII + activated microglial, CD4⁺ T cells, and neutrophil infiltration, while promoting CD19 + B and CD8 + T cells. Similar immunomodulatory effects were observed in the periphery, including restoration of follicular B cells and reduced neutrophil frequencies. Mechanistically, aSyn exposure downregulated activating NK ligands and upregulated inhibitory receptor ligand mQa1b, along with p21 induction in microglia, suggesting a senescence-associated, immune-evasive phenotype that may contribute to reduced therapeutic efficacy at later disease stage. Conclusions Our study provides direct evidence of NK cells exerting neuroprotective and immunomodulatory effect in a preclinical model of synucleinopathy. These findings support NK cell transfer as a novel therapeutic strategy for PD and related neurodegenerative disorders.

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