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J Mol Biol. 2019 May 31;431(12):2248-2265. doi: 10.1016/j.jmb.2019.04.019. Epub 2019 Apr 30.

The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease.

Author information

1
Sussex Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 6NN, UK.
2
Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex , BN1 6NN, UK.
3
Sussex Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 6NN, UK; Chemistry Department, College of Science, Mustansiriyah University, Baghdad, Iraq.
4
School of Biosciences, University of Kent, Canterbury, England CT2 7NJ, UK.
5
School of Biological Sciences, Institute of Biological and Biomedical Sciences, Faculty of Science, University of Portsmouth, Portsmouth, Hampshire PO1 2DY, UK.
6
Sussex Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 6NN, UK. Electronic address: L.C.Serpell@sussex.ac.uk.

Abstract

Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an α-helical, 299-amino-acid protein. Homozygosity for the ε4 allele is the major genetic risk factor for developing late-onset Alzheimer's disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158, and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerization state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small-angle x-ray scattering, analytical ultracentrifugation, circular dichroism, x-ray fiber diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerize to form wavy filaments, which do not share the characteristics of cross-β amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis, and these results open opportunities for uncovering new triggers for AD onset.

KEYWORDS:

Alzheimer's disease; alpha-helix; analytical ultracentrifugation; apolipoprotein E; small-angle x-ray scattering

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