title: The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.
abstract: The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found in AD patients' brain. We have previously shown that a specific apoE4 fragment, 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 apoE fragments to promote Aβ42 intraneuronal accumulation is specific for both the apoE4 isoform and the particular structural and thermodynamic properties of the fragment.
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dafnis
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Letta
authors.initials: L
authors.lastname: Argyri
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Marina
authors.initials: M
authors.lastname: Sagnou
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Tzinia
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Effie C
authors.initials: EC
authors.lastname: Tsilibary
authors.affiliation: Protein Chemistry Laboratory, Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Stratikos
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens 15310, Greece.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Chroni
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000378:metabolism*; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055550:Protein Stability; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; C000612345:ApoE protein, human; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42)