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.
Highlights
Alzheimer’s Disease (AD), characterized by accumulation of beta-amyloid (Aβ) plaques in the brain, can be caused by age-related failures to clear Beta-amyloid peptide (Aβ) from the brain through pathways that involve the cerebrovasculature
high-density lipoproteins (HDL) suppresses aβ-mediated monocyte adhesion to endothelial cells (EC) in three-dimensional dynamic engineered human vessels To mimic the complexity of native cell-cell and/or cellmatrix interactions observed in native human vessels, we used innovative tissue engineering technology to generate in vitro 3 dimensional (3D) human vessels composed of primary human umbilical vein ECs (HUVEC) and primary human smooth muscle cells (SMC) to maximize translational relevance of our studies relative to in vitro studies that solely use traditional static cell culture models
As Aβ originates within the brain and the primary pathways by which Aβ is cleared from the brain involve cerebral vessels [7], we showed that the human brain microvascular endothelial cell line hCMEC/ Human cortical microvascular endothelial cell line D3 (D3), a commonly used cell line for in vitro studies of the blood brain barrier (BBB) [20], exhibit increased peripheral blood mononuclear cell (PBMC) adhesion upon Aβ treatment and that this too is attenuated by HDL (Fig. 2c,d)
Summary
Alzheimer’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. 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. The elevated concentration of plasma high-density lipoprotein cholesterol (HDL-C), which is associated with reduced cardiovascular disease risk [11], is negatively correlated with cognitive decline [12]. Transgenic overexpression of human apoA-I, the major protein component on HDL, from its endogenous promoter in the liver and intestine, reduces neuroinflammation, improves cognitive function and selectively reduces cerebrovascular amyloid in the APP/ PS1 model of amyloidosis, whereas deletion of apoA-I, the major protein component of HDL, has the opposite effects [13, 14]. We recently reported that a single intravenous injection of reconstituted HDL reduces soluble brain Aβ40 and Aβ42 levels after 24 h in symptomatic APP/PS1 mice [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
