The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease. Issue 12 (31st May 2019)

• Record Type: Journal Article
• Authors: Raulin, Ana-Caroline; Kraft, Lucas; Al-Hilaly, Youssra K.; Xue, Wei-Feng; McGeehan, John E.; Atack, John R.; Serpell, Louise
• Is Part Of: Journal of molecular biology. Volume 431:Issue 12(2019)
• Page Start: 2248
• Page End: 2265
• Publication Date: 2019-05-31
• Subjects: AD Alzheimer's disease -- ApoE apolipoproteinE -- TEM transmission electron microscopy -- SAXS small-angle x-ray scattering -- AUC analytical ultracentrifugation -- CD circular dichroism -- SEC size exclusion chromatography -- MALS multi-angle light scattering -- PB phosphate buffer -- SDS sodium dodecylsulfate -- GuHCl guanidine hydrochloride -- ThT thioflavin T; apolipoprotein E -- Alzheimer's disease -- small-angle x-ray scattering -- analytical ultracentrifugation -- alpha-helix; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2019.04.019
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical abstract: Unlabelled Image Highlights: There are three apolipoprotein E isoforms, and E4E4 increases the risk for Alzheimer's disease. ApoE2, E3 and E4 share a quaternary, tertiary and secondary structures, and stability. ApoE4 forms non-amyloid-like filaments, while ApoE2 and E3 do not. Assembly of E4 may play a role increased risk of late-onset Alzheimer's disease.