Abstract
High-density lipoprotein (HDL) plays a vital role in lipid metabolism and anti-inflammatory activities; a dysfunctional HDL impairs cholesterol efflux pathways. To understand HDL’s role in patients with Alzheimer’s disease (AD), we analyzed the chemical properties and function. HDL from AD patients (AD-HDL) was separated into five subfractions, H1–H5, using fast-protein liquid chromatography equipped with an anion-exchange column. Subfraction H5, defined as the most electronegative HDL, was increased 5.5-fold in AD-HDL (23.48 ± 17.83%) in comparison with the control HDL (4.24 ± 3.22%). By liquid chromatography mass spectrometry (LC/MSE), AD-HDL showed that the level of apolipoprotein (apo)CIII was elevated but sphingosine-1-phosphate (S1P)-associated apoM and anti-oxidative paraoxonase 1 (PON1) were reduced. AD-HDL showed a lower cholesterol efflux capacity that was associated with the post-translational oxidation of apoAI. Exposure of murine macrophage cell line, RAW 264.7, to AD-HDL induced a vibrant expression of ganglioside GM1 in colocalization with apoCIII on lipid rafts alongside a concomitant increase of tumor necrosis factor-α (TNF-α) detectable in the cultured medium. In conclusion, AD-HDL had a higher proportion of H5, an apoCIII-rich electronegative HDL subfraction. The associated increase in pro-inflammatory (apoCIII, TNF-α) components might favor Amyloid β assembly and neural inflammation. A compromised cholesterol efflux capacity of AD-HDL may also contribute to cognitive impairment.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disease affecting more than 35 million people worldwide [1]
The total cholesterol (T-CHOL), High-density lipoprotein (HDL)-C and LDL-C were relatively decreased in the AD group but within the reference range
The functional protein contents albumin was reduced; in contrast, the pro-inflammatory components such as apoCIII, and the oxidation of apoAI and apoE were enhanced in AD-HDL
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disease affecting more than 35 million people worldwide [1]. Due to the proteolytic activity of β-secretase (BACE), amyloid precursor protein (APP) can be cleaved into Amyloid Aβ42 [5]. The other identifiable feature is hyper-phosphorylated and abnormally folded Tau protein within the neurons [6]. Apart from these clinically distinct features, many reports show that lipid metabolism dysregulation is associated with Alzheimer’s disease [7,8,9,10,11]. Ceramide regulates the molecular stability of BACE to promote Aβ42 overproduction, which enhances sphingomyelinase activity to overproduce ceramide
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