Natural Killer Subset Changes and Vascular Endothelial Growth Factor-A Plasma Profile in Progressive Supranuclear Palsy: The NKscape Study

Background Emerging evidence implicates neuroinflammation in progressive supranuclear palsy (PSP) pathophysiology, with elevated cyto-chemokines suggesting natural killer (NK) cell involvement.Methods We characterized peripheral NK in PSP (N = 11) versus Parkinson's disease (PD, N = 10) and healthy controls (HC, N = 8) at both immunophenotypic and transcriptional levels.Results PSP patients showed significantly reduced CD3-CD56 + NK frequency (1.35% +/- 0.98%) compared with HC (2.96% +/- 1.14%) and PD (2.03% +/- 0.86%), specifically affecting the immunoregulatory CD56brightCD16-/dim subset. PSP NK cells exhibited elevated CX3CR1 expression, suggesting enhanced migratory capacity toward inflamed tissues. Transcriptomic analysis of primary NK cells revealed 208 DEG with significant enrichment in angiogenesis pathways, particularly vascular endothelial growth factor-A (VEGF-A). Plasma VEGF-A measurements demonstrated a disease-specific pattern: inverse correlation with severity in PSP versus direct correlation in PD.Conclusions These findings identify a potentially disease-specific transcriptional signature with repercussions on the cyto-chemokine plasma profile. Further investigation of the NK cell-mediated immune response in PSP may provide new insights into disease mechanisms and open avenues for immunomodulatory therapeutic strategies.