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The molecular basis for apolipoprotein E4 as the major risk factor for late onset Alzheimer's disease
Version 2 2023-06-07, 08:22
Version 1 2023-06-07, 06:32
journal contribution
posted on 2023-06-07, 08:22 authored by Ana Raulin, Lucas Kraft, Youssra Al-Hilaly, Wei-Feng Xue, John E McGeehan, John R Atack, Louise SerpellLouise SerpellApolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an ?-helical, 299-amino acid protein. Homozygosity for the e4 allele is the major 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, oligomerisation 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 fibre 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 polymerise to form wavy filaments which do not share the characteristics of cross-? 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.
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Publication status
- Published
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- Published version
Journal
Journal of Molecular BiologyISSN
0022-2836Publisher
ElsevierExternal DOI
Issue
12Volume
431Page range
2248-2265Department affiliated with
- BSMS Neuroscience Publications
Research groups affiliated with
- Dementia Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-05-09First Open Access (FOA) Date
2019-06-11First Compliant Deposit (FCD) Date
2019-05-08Usage metrics
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