Clinical Correlates Identify ProBDNF and Thrombo-Inflammatory Markers as Key Predictors of Circulating p75NTR Extracellular Domain Levels in Older Adults.

Samuel Fleury,David Busseuil,Jean-Christophe Bélanger,Mélanie Welman,Bianca D’Antono,Imane Boukhatem,Marie Lordkipanidzé,Jean-Claude Tardif,Lawrence Ledoux-Hutchinson,Mireille E Schnitzer

doi:10.3389/fnagi.2022.821865

Abstract

The p75NTR receptor binds all neurotrophins and is mostly known for its role in neuronal survival and apoptosis. Recently, the extracellular domain (ECD) of p75NTR has been reported in plasma, its levels being dysregulated in numerous neurological diseases. However, the factors associated with p75NTR ECD levels remain unknown. We investigated clinical correlates of plasma p75NTR ECD levels in older adults without clinically manifested neurological disorders. Circulating p75NTR levels were measured by enzyme-linked immunosorbent assay in plasma obtained from participants in the BEL-AGE cohort (n = 1,280). Determinants of plasma p75NTR ECD levels were explored using linear and non-linear statistical models. Plasma p75NTR ECD levels were higher in male participants; were positively correlated with circulating concentrations of pro-brain-derived neurotrophic factor, and inflammatory markers interleukin-6 and CD40 Ligand; and were negatively correlated with the platelet activation marker P-selectin. While most individuals had p75NTR levels ranging from 43 to 358 pg/ml, high p75NTR levels reaching up to 9,000 pg/ml were detectable in a subgroup representing 15% of the individuals studied. In this cohort of older adults without clinically manifested neurological disorders, there was no association between plasma p75NTR ECD levels and cognitive performance, as assessed by the Montreal Cognitive Assessment score. The physiological relevance of high p75NTR ECD levels in plasma warrants further investigation. Further research assessing the source of circulating p75NTR is needed for a deeper understanding of the direction of effect, and to investigate whether high p75NTR ECD levels are predictive biomarkers or consequences of neuropathology.

Highlights

The brain-derived neurotrophic factor (BDNF) is a protein from the neurotrophin family that is first synthesized as a proprotein, proBDNF, which is cleaved to produce mature BDNF (Lu et al, 2005; Lessmann and Brigadski, 2009)
While proBDNF is mostly found in plasma, BDNF is stored in platelets and secreted upon platelet activation (Rosenfeld et al, 1995; Pliego-Rivero et al, 1997; Fujimura et al, 2002; ATLAS Collaboration, 2014; Le Blanc et al, 2020)
Circulating p75NTR levels varied between 40 and 9,207 pg/ml and there was no difference in p75NTR extracellular domain (ECD) levels between coronary artery disease (CAD) and non-CAD individuals (Figure 1A)

Summary

Introduction

The brain-derived neurotrophic factor (BDNF) is a protein from the neurotrophin family that is first synthesized as a proprotein, proBDNF, which is cleaved to produce mature BDNF (Lu et al, 2005; Lessmann and Brigadski, 2009). Expression of proBDNF and BDNF is not limited to the central nervous system (Barde et al, 1982), as they are both found in higher concentrations in blood. The p75NTR receptor is expressed outside the central nervous system and found on peripheral blood mononuclear cells, on endothelial cells where its expression is increased by ischemia, and on platelets (Salis et al, 2004; Brunelli et al, 2012; Minnone et al, 2017; Fleury et al, 2021). Circulating p75NTR ECD levels have the potential to help diagnose several neurological diseases (Chilton et al, 2004; Jiao et al, 2015; Chen et al, 2017; Shi et al, 2021). The factors associated with p75NTR ECD levels in blood remain largely unknown. We sought to investigate the determinants of circulating p75NTR levels in a large cohort of older adults

Methods

Results

Conclusion