Immunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy.

Background: Peripheral immune cells critically contribute to the clinical‐pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. Objective: Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. Methods: Seventy‐one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil‐to‐lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2‐related factor (NRF2)/heme oxygenase 1 (HO‐1) pathway and the total tau (t‐tau) and phosphorylated tau (p‐tau) proteins. Case–control comparison and correlation analyses were performed. Results: PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO‐1 pathway activated in patients. P‐tau, but not t‐tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. Conclusions: PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO‐1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p‐tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]