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

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.

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…Some lipoproteins have protective effects, while others have AD enhancing properties. For example, HDL has been shown to be protective by improving Aβ clearance, delaying Aβ fibrillization, suppressing vascular inflammation, and inducing endothelial nitric oxide production (Button et al, 2019).…”

Alzheimer's disease in the gut—Major changes in the gut of 5xFAD model mice with ApoA1 as potential key player

“…81 Recently, an investigation of ApoA1 deficiency in APP/PS1 AD model mice revealed increased total and vascular A-beta deposition as well as astrocytosis in comparison to hemizygous controls. 82 This suggests that ApoA1-containing HDL can reduce amyloid-driven pathology and astrocyte reactivity. This effect might be due to ApoA1s ability to bind A-beta and accelerate the formation of higher molecular aggregates which are not neurotoxic.…”

HDL from an Alzheimer's disease perspective

“…These engineered tissues display histological features of native peripheral and cerebral arteries and can be used to model CAA and vascular inflammation. This model can also be used to interrogate four beneficial functions of HDL on cerebral vessels, namely preventing Aβ-induced endothelium activation, reducing Aβ vascular accumulation, maintaining Aβ in a soluble state, and inducing endothelial NO secretion [123 ▪▪ ,124 ▪▪ ,125] (Fig. 1).…”