Vasoprotective Functions of High-Density Lipoproteins Relevant to Alzheimer's Disease Are Partially Conserved in Apolipoprotein B-Depleted Plasma.

Emily Button,Jérôme Robert,Harleen Cheema,Cheryl Wellington,Megan Gilmour,Andrew Agbay,Emma Martin

doi:10.3390/ijms20030462

Emily Button, Jérôme Robert + Show 5 more

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https://doi.org/10.3390/ijms20030462

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Abstract

High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular benefits of HDL in healthy humans may partly explain epidemiological evidence suggesting a protective association of circulating HDL levels against Alzheimer’s Disease (AD) risk. As several methods exist to prepare HDL from plasma, here we compared cerebrovascular functions relevant to AD using HDL isolated by density gradient ultracentrifugation relative to apoB-depleted plasma prepared by polyethylene-glycol precipitation, a common high-throughput method to evaluate HDL cholesterol efflux capacity in clinical biospecimens. We found that apoB-depleted plasma was functionally equivalent to HDL isolated by ultracentrifugation in terms of its ability to reduce vascular Aβ accumulation, suppress TNFα-induced vascular inflammation and delay Aβ fibrillization. However, only HDL isolated by ultracentrifugation was able to suppress Aβ-induced vascular inflammation, improve Aβ clearance, and induce endothelial nitric oxide production.

Highlights

An emerging area of interest for high-density lipoprotein (HDL) research is its role in neurodegenerative disease
Preclinical studies show that HDL-deficient Alzheimer’s disease (AD) mice, generated by genetic deletion of apoA-I, have increased vascular Aβ deposition, known as cerebral amyloid angiopathy (CAA), and worse cognitive performance compared to AD mice with normal HDL levels [10], whereas AD mice overexpressing apoA-I from its native promoter show the opposite phenotype with an additional improvement in central nervous system (CNS) inflammation [11]
We developed an in vitro, 3D model of CAA using primary human endothelial cells (EC) and smooth muscle cells (SMC) cells cultured under native-like flow conditions (Figure S1a–c) and showed that when HDL isolated by ultracentrifugation is circulated through the lumen of the arteries, the accumulation of Aβ42 in the arterial wall is prevented [15]

Summary

Introduction

An emerging area of interest for high-density lipoprotein (HDL) research is its role in neurodegenerative disease. Preclinical studies show that HDL-deficient AD mice, generated by genetic deletion of apoA-I, have increased vascular Aβ deposition, known as CAA, and worse cognitive performance compared to AD mice with normal HDL levels [10], whereas AD mice overexpressing apoA-I from its native promoter show the opposite phenotype with an additional improvement in central nervous system (CNS) inflammation [11]. Oral treatment of AD mice with an apoA-I mimetic improves memory and reduces amyloid burden [12], intravenous treatment with reconstituted human HDL or recombinant apoA-I Milano reduces soluble Aβ levels in the brains of AD mice [13,14], and either treatment reduces CNS inflammation [12,14]

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