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.