Human Blood Serum Impacts Permeability of the Blood‐Brain Barrier in a Sex‐ and Age‐ Dependent Manner

Abstract

The blood‐brain barrier (BBB), a semi‐permeable fence between the brain and the blood, maintains homeostatic balance of substances entering and leaving the brain. In the last decade, the causes and consequences of BBB dysfunction have been recognized as the central component of the development and progression of brain‐related illnesses such as Alzheimer's disease (AD), multiple sclerosis (MS), and schizophrenia (SCZ). In these disorders, pathologic BBB leakiness is often caused by changes in the local cellular milieu on the brain‐side as well as on the blood‐side of the BBB. On the brain‐side, injury to neurons, astrocytes, microglia, and pericytes can lead to BBB leakiness, while on the blood‐side, pathophysiologic levels of circulating factors such as hormones, inflammatory cytokines, and immune cells can significantly alter BBB permeability. The goal of this study was to test whether blood serum, which reflects the circulating milieu in the body, can directly alter BBB integrity. We tested the hypothesis that blood serum of patients with secondary progressive multiple sclerosis (SPMS) will increase BBB permeability compared to healthy controls.To test the direct impact of blood serum on BBB integrity, we used three‐dimensional Neurovascular Units (3D NVUs). This in vitro model of the BBB integrates endothelial, neuronal, astrocytic, and microglial cells into a three‐dimensional platform, that allows for the assessment of transendothelial electrical resistance (TEER, Ω cm2). Blood serum of four SPMS patients (two men, two women) and four matched healthy controls (two men, two women) were purchased from PrecisionMed, Inc., and diluted to 40% with cell culture media for testing. TEER was recorded immediately prior to serum exposure (baseline), and again at 24 hours after serum treatment. TEER values were normalized to baseline prior to analysis. The protein levels of 100 different serum cytokines were measured in undiluted serum samples using the Human Cytokine Proteome Profiler (R&D Systems).Stepwise multiple regression analysis revealed that age and sex of the individual were strong predictors of the change in TEER, with serum from female and younger individuals inducing a greater change in TEER (R2=0.81, p=0.01). Presence of SPMS, and levels of cytokines were poor predictors of BBB permeability as measured by TEER. This preliminary study demonstrates that the 3D NVU may be a useful tool in future investigations of the effects of blood serum on BBB integrity.Support or Funding InformationThis project was funded by the TATRC AMEDD Advanced Medical Technology Initiative grant. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.