Abstract
The association between apolipoprotein E (apoE) and amyloid-β peptide (Aβ) may significantly impact the function of both proteins, thus affecting the etiology of Alzheimer's disease (AD). However, apoE/Aβ interactions remain fundamentally defined by the stringency of the detection method. Here we use size exclusion chromatography (SEC) as a non-stringent approach to the detection of apoE/Aβ interactions in solution, specifically apoE and both endogenous and exogenous Aβ from plasma, CSF and astrocyte conditioned media. By SEC analysis, Aβ association with plasma and CNS lipoproteins is apoE-dependent. While endogenous Aβ elutes to specific human plasma lipoproteins distinct from those containing apoE, it is the apoE-containing lipoproteins that absorb excess amounts of exogenous Aβ40. In human CSF, apoE, endogenous Aβ and phospholipid elute in an almost identical profile, as do apoE, exogenous Aβ and phospholipid from astrocyte conditioned media. Combining SEC fractionation with subsequent analysis for SDS-stable apoE/Aβ complex reveals that apoE-containing astrocyte lipoproteins exhibit the most robust interactions with Aβ. Thus, standardization of the methods for detecting apoE/Aβ complex is necessary to determine its functional significance in the neuropathology characteristic of AD. Importantly, a systematic understanding of the role of apoE-containing plasma and CNS lipoproteins in Aβ homeostasis could potentially contribute to identifying a plasma biomarker currently over-looked because it has multiple components.
Highlights
Two key proteins involved in Alzheimer’s disease (AD) are found circulating in both peripheral and CNS fluids associated with lipoprotein particles: apolipoprotein E and amyloid-β peptide (Aβ)
Human plasma from apolipoprotein E (apoE) genotyped donors (ε2/2, ε3/3, ε4/4) was fractionated by size exclusion chromatography (SEC) using fast protein liquid chromatography (FPLC) to determine whether the isoforms of human apoE affect endogenous Aβ association with plasma lipoproteins
Endogenous Aβ clearly has an elution profile that indicates a specific preference for certain classes of lipoproteins in the plasma, this profile does not match the apoE profile
Summary
Two key proteins involved in Alzheimer’s disease (AD) are found circulating in both peripheral and CNS fluids associated with lipoprotein particles: apolipoprotein E (apoE) and amyloid-β peptide (Aβ). ApoE expression is highest in the liver, followed by apoE expression in the brain. ApoE-containing plasma lipoproteins, synthesized primarily by the liver, do not cross the blood-brain barrier (BBB). ApoE is the major lipoprotein forming apolipoprotein produced in the brain (For review, [4]); secreted primarily by astrocytes as nascent apoE-containing discoidal particles [5, 6]. ApoE associates with lipoproteins to provide structural stability and serve as a ligand for receptormediated uptake of lipoproteins, facilitating cellular metabolism of cholesterol and lipids (for review, [7])
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