title: Synthetic Models of Quasi-Stable Amyloid β40 Oligomers with Significant Neurotoxicity.
abstract: The formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Aβ42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Aβ42, Aβ40 dimers can also contribute to AD progression because of the more abundance of Aβ40 monomer in biological fluids. Here, we describe the synthesis and characterization of three dimer models of the toxic-conformation constrained E22P-Aβ40 using l,l-2,6-diaminopimeric acid (DAP) or l,l-2,8-diaminoazelaic acid (DAZ) linker at position 30, which is incorporated into the intermolecular parallel β-sheet region, and DAP at position 38 in the C-terminal hydrophobic core. E22P-A30DAP-Aβ40 dimer (1) and E22P-A30DAZ-Aβ40 dimer (2) existed mainly in oligomeric states even after 2 weeks incubation without forming fibrils, unlike the corresponding monomer. Their neurotoxicity toward SH-SY5Y neuroblastoma cells was very weak. In contrast, E22P-G38DAP-Aβ40 dimer (3) formed β-sheet-rich oligomeric aggregates, and exhibited more potent neurotoxicity than the corresponding monomer. Ion mobility-mass spectrometry suggested that high molecular-weight oligomers (12-24-mer) of 3 form, but not for 1 and 2 after 4 h incubation. These findings indicate that formation of the hydrophobic core at the C-terminus, rather than intermolecular parallel β-sheet, triggers the formation of toxic Aβ oligomers. Compound 3 may be a suitable model for studying the etiology of Alzheimer's disease.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Irie
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Hanaki
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hanaki
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: National Institute of Biomedical Innovation, Health and Nutrition , Osaka 567-0085, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Monobe
authors.affiliation: National Institute of Biomedical Innovation, Health and Nutrition , Osaka 567-0085, Japan.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Takai
authors.affiliation: National Institute of Biomedical Innovation, Health and Nutrition , Osaka 567-0085, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Akagi
authors.affiliation: Nihon Waters K. K. , Tokyo 140-0001, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Kawase
authors.affiliation: Nihon Waters K. K. , Tokyo 140-0001, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Kazuhiro
authors.identifier: 0000-0001-7109-8568
authors.initials: K
authors.lastname: Irie
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D002460:Cell Line; D002942:Circular Dichroism; D006801:Humans; D013058:Mass Spectrometry; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)
keywords: Amyloid β; dimer; ion mobility−mass spectrometry; neurotoxicity; oligomer; β-sheet