Nanoliposomes protect against human arteriole endothelial dysfunction induced by β-amyloid peptide

Abstract

We tested whether nanoliposomes containing phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) prevent bamyloid 1-42 (Ab42) fibrillation and Ab42-induced human arteriole endothelial dysfunction. NLPA abolished Ab42 fibril formation (thioflavin-T fluorescence/electron microscopy). In ex-vivo human adipose and leptomeningeal arterioles, Ab42 impaired dilator response to acetylcholine that was reversed by NLPA; this protection was abolished by L-NGnitroarginine methyl ester. Ab42 reduced human umbilical vein endothelial cell NO production that was restored by NLPA. Nanoliposomes prevented Ab42 amyloid formation, reversed Ab42-induced human microvascular endothelial dysfunction and may be useful in Alzheimer's disease.

Monosialoganglioside‐Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins

“…The dose of LC was chosen because it was within known physiological concentrations of LC in patients . The NLGM1 concentration was chosen because it was similar to the concentration of a phosphatidic acid–containing nanoliposome that conferred a protective effect against β‐amyloid and LC …”

“…Superoxide production was detected by fluorescent reaction of dihydroethidium (Molecular Probes), whereas peroxynitrite production was detected using coumarin boronic acid pinacolate ester (Cayman Chemical), similar to previous methods . HUVECs were seeded into 12‐well plates with glass coverslips in the bottom 16 to 20 hours before undergoing treatment with vehicle control, LC with or without NLGM1, or NLGM1 for 18 to 20 hours.…”

“…They may be the ideal type of nanoparticles for disease treatment because their compositions can be varied to produce desired physiological effects, and they can be loaded with therapeutic cargo; in addition to this structural versatility, they have the advantage of being nonimmunogenic and fully biodegradable and have low cytotoxicity . We recently showed that phosphatidic acid–containing nanoliposomes restored endothelial function in microvessels exposed to LC and preserved endothelial cell viability, effects that parallel beneficial protection in human microvessels exposed to β‐amyloid peptides . Monosialogangliosides (GM1 ganglioside) are glycosphingolipids found in plasma membranes and may have a potential advantage over phosphatidic acid in AL because they were found to have antioxidant properties in brain and cardiac tissues and were shown to reduce myocardial ischemia–reperfusion injury, attributes that could be beneficial in reversing LC‐induced oxidative stress and cell injury.…”

“…9,11 We recently showed that phosphatidic acid-containing nanoliposomes restored endothelial function in microvessels exposed to LC and preserved endothelial cell viability, 7 effects that parallel beneficial protection in human microvessels exposed to b-amyloid peptides. 12 Monosialogangliosides (GM1 ganglioside) are glycosphingolipids found in plasma membranes and may have a potential advantage over phosphatidic acid in AL because they were found to have antioxidant properties in brain and cardiac tissues [13][14][15] and were shown to reduce myocardial ischemia-reperfusion injury, 14 attributes that could be beneficial in reversing LC-induced oxidative stress and cell injury. Our group formulated GM1 ganglioside-containing nanoliposomes (NLGM1), and the aims of this study were to test the hypothesis that NLGM1 protects against LC-induced human endothelial dysfunction and to identify the potential mechanism underlying the protection.…”

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

“…Ab fibrillization was measured as described (Truran et al, 2016). Briefly, 10 ml of RIPA homogenized tissue was mixed with 90 ml of 20 mM Thioflavin-T (Sigma-Aldrich) in 150 mM NaCl with 5 mM HEPES, pH 7.4 in black 96-well plates.…”