Abstract
Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.
Highlights
Apolipoprotein E (ApoE) is a lipid transport protein that exists in the three isoforms ApoE2, ApoE3, and ApoE4 that are encoded by the three alleles ε2, ε3, and ε4, respectively [1]
In order to assess the interference of ApoE with Islet amyloid polypeptide (IAPP) amyloidogenesis, we monitored the kinetics of IAPP aggregation in the presence of ApoE variants by using a ThT binding assay
We studied the ability of ApoE variants (ApoE2, ApoE3, and ApoE4) to interfere with IAPP amyloid formation in vitro and assessed their effect on IAPP-induced cytotoxicity on human blood vessel pericytes
Summary
Apolipoprotein E (ApoE) is a lipid transport protein that exists in the three isoforms ApoE2, ApoE3, and ApoE4 that are encoded by the three alleles ε2, ε3, and ε4, respectively [1]. The amino acid differences between the three isoforms of ApoE are limited to positions 112 and 158, where ApoE2 has Cys residues at both positions; ApoE3 has a Cys at position 112 and an Arg at position 158, and ApoE4 has Arg residues at both of these positions [1,4,5]. A recent study by Raulin et al shows that there are no significant differences between the recombinant ApoE variants at the structural or conformational level, ApoE4 has a higher propensity to form non-amyloid aggregates [6]
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