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

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.

Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

“…However, it is clear from our results that besides the isoform differences, the concentration of ApoE is important in protecting the cells from cytotoxicity because at lower concentrations, all ApoE variants demonstrated reduced efficiency over time, although to a different extent and with the most pronounced decline being seen for the ApoE4 variant. The propensity of ApoE4 to aggregate shown recently [6] could contribute to this decline by reducing even more the concentration of functionally active molecules. These data are also consistent with the findings of significantly reduced expression of the ApoE4 variant in vivo [36,37], which might be an explanation for its association with AD pathology.…”

“…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]. These seemingly small differences in the sequence have a great impact on ApoE functionality [1,6]. The information about the structural and conformational differences between the ApoE variants is controversial.…”

“…Moreover, differences in stability and conformation between the ApoEs have been suggested [9,10], indicating that ApoE4 is less stable and can aggregate into amyloid-like fibrils [10]. However, 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, although ApoE4 has a higher propensity to form non-amyloid aggregates [6].…”

Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42

“…4.C), largely reflecting the loss of oligomerization and, to a smaller extent, avidity, since full-length ApoE3 is a tetramer while ApoE3 1-238 is a monomer (Fig. S2.B and [32,37]). Because ApoE3 1-238 is a monomer, we were able to accurately model the kinetic data 1:1, revealing a K D = 696 ± 27 nM (compared to 440 nM for full-length ApoE3) ( Fig.…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…30 The late-onset sporadic form (LOAD) of Alzheimer's disease (AD) [31][32][33] accounts for >90% of disease cases. 31,[34][35][36] Along with advanced aging, 23,[37][38][39][40][41][42][43] inheritance of the apolipoprotein E4 allele (also called APOE4 or APOEe4) remains the most significant known genetic risk factor for LOAD. The risk is higher and the age at onset of dementia is younger for individuals carrying multiple copies of APOE4, whereas other APOE alleles are considered protective.…”