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. 2022 Feb 21:14:821865.
doi: 10.3389/fnagi.2022.821865. eCollection 2022.

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

Affiliations

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

Samuel Fleury et al. Front Aging Neurosci. .

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.

Keywords: inflammation; neurotrophhic factors; p75NTR receptor; plasma; proBDNF.

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Conflict of interest statement

ML has received speaker fees from Bayer; has participated in industry-funded trials from Idorsia; has served on advisory boards for Servier and JAMP/Orimed Pharma; and has received in-kind and financial support for investigator-initiated grants from Leo Pharma, Roche Diagnostics, Aggredyne, and Fujimori Kogyo. MS has received speaker fees from Biogen and consultant fees from Carebook Technologies Inc. J-CT reports research grants from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, and Sanofi; honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Pharmaceuticals, and Pendopharm; and minor equity interest in DalCor Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
p75NTR distribution and correlation with coronary artery disease. (A) Soluble p75NTR extracellular domain (ECD) levels in participants without (blue, n = 607) and with coronary artery disease (CAD, red, n = 673). (B) Spearman correlation between The Montreal Cognitive Assessment (MoCA) score and plasma p75NTR ECD levels in non-CAD (blue, n = 607) and CAD (red, n = 673) participants. (C) Distribution of ln-transformed plasma p75NTR ECD levels (bars, left y axis) as well as the non-transformed median p75NTR plasma levels (red curve, right y axis), n = 1,280. The 85th percentile was chosen as cut-off because levels started to rise exponentially around this percentile.
FIGURE 2
FIGURE 2
Correlation between p75NTR and proBDNF levels in BEL-AGE participants. Correlation between ln-transformed levels of plasma p75NTR ECD and proBDNF was assessed using Spearman correlation in panel (A) the whole BEL-AGE cohort (n = 1,280), (B) in male participants (n = 770) and (C) in female participants (n = 510). Spearman’s coefficient and p-values are displayed. Difference between Spearman’s coefficients in male and female individuals is not significant. Interplay between p75NTR, proBDNF, P-selectin, and IL-6 levels in plasma, in panel (D) the whole cohort (n = 1,280), (E) male participants (n = 770) and (F) female participants (n = 510).

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