Interaction with Amyloid β Peptide Compromises the Lipid Binding Function of Apolipoprotein E

Abstract

Apolipoprotein (apo) E is an exchangeable apolipoprotein that plays an integral role in cholesterol transport in the plasma and the brain. It is also associated with protein misfolding or amyloid proteopathy of the beta amyloid peptide (Abeta) in Alzheimer's disease (AD) and cerebral amyloid angiopathy. The C-terminal domain (CT) of apoE encompasses two types of amphipathic alpha helices: a class A helix (residues 216-266) and a class G* helix (residues 273-299). This domain also harbors high-affinity lipoprotein binding and apoE self-association sites that possibly overlap. The objective of this study is to examine if the neurotoxic oligomeric Abeta interacts with apoE CT and if this association affects the lipoprotein binding function of recombinant human apoE CT. Site-specific fluorescence labeling of single cysteine-containing apoE CT variants with donor probes were employed to identify the binding of Abeta bearing an acceptor probe by intermolecular fluorescence resonance energy-transfer analysis. A higher efficiency of energy transfer was noted with probes located in the class A helix than with those located in the class G* helix of apoE CT. In addition, incubation of apoE CT with Abeta severely impaired the lipid binding ability and the overall amount of lipid-associated apoE CT. However, when apoE CT is present in a lipid-bound state, Abeta appears to be localized within the lipid milieu of the lipoprotein particle and not associated with any specific segments of the protein. When our data are taken together, they suggest that Abeta association compromises the fundamental lipoprotein binding function of apoE, which may have implications not only in terms of amyloid buildup but also in terms of the accumulation of cholesterol at extracellular sites.

Premature Ligand-Receptor Interaction during Biosynthesis Limits the Production of Growth Factor Midkine and Its Receptor LDL Receptor-related Protein 1

“…Interestingly, both MK and apoE can bind to A␤, and MK, apoE, and LRP1 are found in senile plaques (39,(41)(42)(43)(44). In addition, MK and apoE also show similar characteristics from the point of view of premature interaction with LRP1: overexpression of apoE or MK suppresses LRP1 maturation and induces LRP1 aggregation, which is restored by RAP expression (20; this study).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Because apoE immunoreactivity is commonly found in amyloid plaques (Namba et al 1991;Wisniewski and Frangione 1992), it is likely that apoE interacts with Ab directly in the human brain. The region of apoE that is responsible for Ab binding is in the carboxy-terminal domain overlapping with the lipid-binding region (Strittmatter et al 1993b;Tamamizu-Kato et al 2008), suggesting that the lipophilic Ab peptide associates with apoE in a process that is analogous to lipid binding. Indeed, Ab binding to apoE compromises its lipid-binding function (Tamamizu-Kato et al 2008).…”

“…The region of apoE that is responsible for Ab binding is in the carboxy-terminal domain overlapping with the lipid-binding region (Strittmatter et al 1993b;Tamamizu-Kato et al 2008), suggesting that the lipophilic Ab peptide associates with apoE in a process that is analogous to lipid binding. Indeed, Ab binding to apoE compromises its lipid-binding function (Tamamizu-Kato et al 2008). Furthermore, Ab peptides modulate the binding of apoE isoforms differently to apoE receptors (Beffert et al 1998;Hone et al 2005).…”

Genetic and Blood Biomarkers of Alzheimer`s Disease

“…Different ApoE isoforms, ApoE 2, ApoE 3, and ApoE 4, differ in their protein structure and binding properties. ApoE also binds to A in the C-terminus, interfering with the lipid binding property of the protein [32]. This interaction which can interrupt the lipid transportation of ApoE, may also contribute to the pathogenesis of AD.…”