Abstract
Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer’s disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aβ). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in Aβ pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE–heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated Aβ uptake and aggregation. ApoE2 increased the cellular internalization of monomeric Aβ, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once Aβ aggregated: while ApoE2 reduced the uptake of Aβ aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4′s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of Aβ pathology.
Highlights
As a 34 kDa glycoprotein constituent of plasma lipoproteins, apolipoprotein E (ApoE)facilitates the cellular transport and metabolism of lipids in the human body [1,2,3]
ApoE exists in three isoforms that differ by only two amino acids: ApoE2 has cysteines located at sites 112 and 158, ApoE3 has a cysteine at site 112 and an arginine at site 158, while ApoE4 has arginines at both sites [5,9]
The cellular uptake of ApoE isoforms was investigated with SDC-specific cellular models [14,16,32]
Summary
As a 34 kDa glycoprotein constituent of plasma lipoproteins, apolipoprotein E (ApoE)facilitates the cellular transport and metabolism of lipids in the human body [1,2,3]. As a 34 kDa glycoprotein constituent of plasma lipoproteins, apolipoprotein E (ApoE). Associated with almost all lipoprotein particles, ApoE mediates the clearance of lipoprotein remnants from the plasma via binding to specific cell surface receptors, including the LDL receptor family members and heparan sulfate proteoglycans (HSPGs) [6,7]. The 299-amino acid-long ApoE has two structural and functional domains: a 22 kDa NH2-terminal domain (amino acids 1–191) and a 10 kDa COOH-terminal domain (residues 216–299) containing the HSPG-binding region (residues 140–150) colocalized with the LDL receptor binding site [3,8]. The cellular transport of lipoproteins is initiated by binding ApoE to the cell surface HSPGs, followed by their internalization mediated either by the LDL receptor or LDL receptor-related protein (LRP) or by the HSPGs alone [8,10,11,12]
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