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.
Highlights
Alzheimer's disease (AD) is the most prevalent dementia, and the sporadic, late-onset form comprises 95% of all AD cases
Initial purification confirmed that ApoE2, E3 and E4 have identical mobilities of 34 kDa by non-reducing sodium dodecylsulfate (SDS)–polyacrylamide gel electrophoresis (PAGE; Fig. S1)
As we extensively dialyzed or buffer exchanged ApoE isoforms into phosphate buffer (PB) prior to stability and aggregation studies, we were interested if dialysis affected ApoE oligomerization in solution
Summary
Alzheimer's disease (AD) is the most prevalent dementia, and the sporadic, late-onset form comprises 95% of all AD cases. The biggest risk factor for developing AD is age, but the ε4 variant of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for the development of late-onset AD. The human APOE gene encodes three major protein isoforms, ApoE2, ApoE3 or ApoE4, that differ from one another at amino acid positions 112 and 158. ApoE4 presents a risk in a gene dose-dependent manner, with ε3/ε4 heterozygotes having a risk increased by three times and ε4/ε4 homozygotes having up to 15 times more chance of developing AD [3]. ApoE3 is the most common isoform, associated with a neutral risk. ApoE2 is under-represented in the population but is thought to be associated with a lower propensity for AD [4]
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