The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.

Ioannis Dafnis,Efstratios Stratikos,Letta Argyri,Effie C Tsilibary,Angeliki Chroni,Marina Sagnou,Athina Tzinia

doi:10.1038/srep30654

Ioannis Dafnis, Efstratios Stratikos + Show 5 more

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https://doi.org/10.1038/srep30654

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Abstract

The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer’s disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found in AD patients’ brain. We have previously shown that a specific apoE4 fragment, apoE4-165, promotes amyloid-peptide beta 42 (Aβ42) accumulation in human neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species formation, two events considered to occur early in AD pathogenesis. Here, we show that these effects are allele-dependent and absolutely require the apoE4 background. Furthermore, the exact length of the fragment is critical since longer or shorter length carboxyl-terminal truncated apoE4 forms do not elicit the same effects. Structural and thermodynamic analyses showed that apoE4-165 has a compact structure, in contrast to other carboxyl-terminal truncated apoE4 forms that are instead destabilized. Compared however to other allelic backgrounds, apoE4-165 is structurally distinct and less thermodynamically stable suggesting that the combination of a well-folded structure with structural plasticity is a unique characteristic of this fragment. Overall, our findings suggest that the ability of apoE fragments to promote Aβ42 intraneuronal accumulation is specific for both the apoE4 isoform and the particular structural and thermodynamic properties of the fragment.

Highlights

Amyloid peptide beta (Aβ) has been proposed to play a key role in the pathogenesis of Alzheimer’s disease (AD)
(designated hereafter as apoE4-165) with a molecular weight of 19 kDa can promote the cellular uptake and accumulation of Aβ42 and leads to formation of reactive oxygen species (ROS)[20]
ApoE4 proteolysis has been proposed to be an early event in the pathogenesis of AD13

Summary

Introduction

Amyloid peptide beta (Aβ) has been proposed to play a key role in the pathogenesis of Alzheimer’s disease (AD). (designated hereafter as apoE4-165) with a molecular weight of 19 kDa (a size within the range of molecular weights of carboxyl-terminal truncated apoE4 fragments found in brains of AD patients14,15,19) can promote the cellular uptake and accumulation of Aβ42 and leads to formation of reactive oxygen species (ROS)[20]. A longer length fragment, apoE4[Δ(186–299)] (designated as apoE4-185), or full-length apoE4 failed to elicit this effect, suggesting that not all apoE4 variants are bioactive[20]. Those findings provided an association between two molecular events, the proteolysis of apoE4 and the intraneuronal presence of Aβ,both of which are considered to be early events in the pathogenesis of AD. Lipid-free apoE is folded into two seemingly independent structural domains separated by a hinge region[22,23]

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