High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture

Abstract

BackgroundAlzheimer’s Disease (AD), characterized by accumulation of beta-amyloid (Aβ) plaques in the brain, can be caused by age-related failures to clear Aβ from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels. Epidemiological studies suggest that HDL is associated with reduced AD risk, and animal model studies support a beneficial role for HDL in selectively reducing cerebrovascular amyloid deposition and neuroinflammation. However, the mechanism by which HDL may protect the cerebrovascular endothelium in the context of AD is not understood.MethodsWe used peripheral blood mononuclear cell adhesion assays in both a highly novel three dimensional (3D) biomimetic model of the human vasculature composed of primary human endothelial cells (EC) and smooth muscle cells cultured under flow conditions, as well as in monolayer cultures of ECs, to study how HDL protects ECs from the detrimental effects of Aβ.ResultsFollowing Aβ addition to the abluminal (brain) side of the vessel, we demonstrate that HDL circulated within the lumen attenuates monocyte adhesion to ECs in this biofidelic vascular model. The mechanism by which HDL suppresses Aβ-mediated monocyte adhesion to ECs was investigated using monotypic EC cultures. We show that HDL reduces Aβ-induced PBMC adhesion to ECs independent of nitric oxide (NO) production, miR-233 and changes in adhesion molecule expression. Rather, HDL acts through scavenger receptor (SR)-BI to block Aβ uptake into ECs and, in cell-free assays, can maintain Aβ in a soluble state. We confirm the role of SR-BI in our bioengineered human vessel.ConclusionOur results define a novel activity of HDL that suppresses Aβ-mediated monocyte adhesion to the cerebrovascular endothelium.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0201-0) contains supplementary material, which is available to authorized users.

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

“…Tubular biodegradable scaffolds (length 1.5 cm and inner diameter 2 mm) were produced as described (Robert et al, 2013a;Robert et al, 2017) with minor modifications. Briefly, non-woven polyglycolic acid (PGA, Biomedical Structure, Warwick, RI) meshes (thickness: 1 mm and density: 70 mg/cc) were dip-coated with polycaprolactone (PCL) and polylactate (PLA) by dipping PGA mesh in a solution of 1.75% (w/w) PCL/PLA/tetrahydrofuran (THF) solution (Sigma-Aldrich, St. Louis, MO), shaped into tubes using heat, and externally coated with a 10% PCL/THF (w/w) solution.…”

Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

“…High‐density lipoproteins (HDLs) have been shown to exert antiinflammatory effects both in vitro and in vivo 80. HDL can downregulate the expression of TLR‐induced proinflammatory cytokines, such as TNF‐α,81 IL‐6,82 IL‐1β,83 and vascular cell adhesion molecule,84 and can increase endothelial nitric oxide synthase production 85. Wang and co‐workers confirmed the antiinflammatory effects of HDL in mice with RA induced by collagen 81.…”

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium

“…In fact, very recently published experimental work (in human-endothelial-cell monolayer cultures as well as in three-dimensional tissue-engineered human vessels) has demonstrated in detail (Robert et al 2017) that HDL, acts via scavenger receptors (class B type I, i.e., SR-BI), to block β-amyloid uptake into endothelial cells --in experimental monolayers as well as, the authors argue, in the human cerebrovascular endothelium (Robert et al 2017). [ These authors also point out that SR-BI is the principal HDL receptor on (human brain microvascular) endothelial cells and activates several HDL-signaling pathways (in addition to mediating selective cholesterol uptake) upon HDL docking.…”