Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Hanaki, Mizuho; Murakami, Kazuma; Katayama, Sumie; Akagi, Ken-ichi; Irie, Kazuhiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 8(2018)
• Page Start: 1538
• Page End: 1546
• Publication Date: 2018-05-01
• Subjects: Aβ amyloid β-protein -- AD Alzheimer's disease -- HFIP 1, 1, 1, 3, 3, 3, -hexafluoroisopropyl alcohol -- HMQC heteronuclear multiple quantum coherence -- HPLC high performance liquid chromatography -- LC–MS liquid chromatography-mass spectrometry -- LC/Q Tof-MS liquid chromatography/quadrupole time-of-flight mass spectrometry -- NMR nuclear magnetic resonance -- PBS phosphate-buffered saline -- SOFAST band-selective optimized flip angle short transient -- TEM transmission electron microscopy -- Th-T thioflavin-T; Alzheimer's disease -- Amyloid β-protein -- Aggregation -- (R)-Apomorphine -- NMR -- LC–MS; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.01.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: ( R )-Apomorphine (1 ) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer's disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC–MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o -quinone form (2 ), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3 ) with o -quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity. 1 H- 15 N SOFAST-HMQC NMR studies suggested that 1 interacts with Arg5, His13, 14, Gln15, and Lys16 of the Aβ42 monomer. These regions form intermolecular β-sheets in Aβ42 aggregates. Since 3 did not perturb the chemical shift of monomeric Aβ42, we performed aggregation experiments using 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol-treated Aβ42 to investigate whether 3 associates with Aβ42 oligomers. Compounds 1 and 3 delayed the onset of the oligomer-driven nucleation phase. Despite their cytotoxicity, they did not exacerbate Aβ42-mediated neurotoxicity in SH-SY5Y neuroblastoma cells. These results demonstrate that extension of the conjugated system in 1 by autoxidation can promote its planarity, which is required for intercalation into the β-sheet of Aβ42 nuclei, thereby suppressing further aggregation.