The ability of Apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific
permalinkScientific Reports - 2016-08-01Dafnis I, Argyn L, Sagnou M, Tzinia A, Tsilibary EC, Stratikos E, Chroni A10.1038/srep30654The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer's disease (AD).
Apolipoprotein E4 is more susceptible to proteolysis than
ApoE3 isoforms and carboxyl-terminal truncated
ApoE4 forms have been found in AD patients' brain. We have previously shown that a specific
ApoE4-165, promotes amyloid-peptide beta 42 (Aβ42) accumulation in human neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species formation, two events considered to occur early in AD pathogenesis. Here, we show that these effects are allele-dependent and absolutely require the
ApoE4 background. Furthermore, the exact length of the fragment is critical since longer or shorter length carboxyl-terminal truncated
ApoE4 forms do not elicit the same effects. Structural and thermodynamic analyses showed that
ApoE4-165 has a compact structure, in contrast to other carboxyl-terminal truncated
ApoE4 forms that are instead destabilized. Compared however to other allelic backgrounds,
ApoE4-165 is structurally distinct and less thermodynamically stable suggesting that the combination of a well-folded structure with structural plasticity is a unique characteristic of this fragment. Overall, our findings suggest that the ability of
ApoEfragments to promote Aβ42 intraneuronal accumulation is specific for both the
ApoE4 isoform and the particular structural and thermodynamic properties of the fragment.