title: Synthesis and characterization of the amyloid β40 dimer model with a linker at position 30 adjacent to the intermolecular β-sheet region.
abstract: Amyloid fibrils in senile plaque mainly consist of the 40-mer and 42-mer amyloid β-proteins (Aβ40 and Aβ42). Although Aβ42 plays more important role in the pathogenesis of Alzheimer's disease (AD), Aβ40 could be involved in the progression of AD pathology because of its large amount. Recent studies revealed that variable sizes of Aβ oligomers contributed to the neuronal death and cognitive dysfunction. However, how large oligomeric species are responsible for AD pathogenesis remains unclear. We previously proposed a toxic dimer model of Aβ with turn structure at positions 22 and 23 using solid-state NMR and systematic proline replacement. Based on this model, we herein show the synthesis and biological activities of an E22P-Aβ40 dimer at position 30, which was connected to l,l-2,6-diaminopimeric acid. The E22P-Aβ40 dimer formed stable 6∼8-mer oligomers without amyloid fibrils, but was not neurotoxic on human neuroblastoma cells. On the other hand, E22P-Aβ40 generated high molecular-weight oligomers into fibrils, and showed the neurotoxicity. These results suggest that such kind of Aβ40 dimer with a parallel β-sheet might not be pathological.
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: Takashi
authors.initials: T
authors.lastname: Suzuki
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: 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: Ken-Ichi
authors.initials: K
authors.lastname: Akagi
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: irie@kais.kyoto-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D011392:Proline
keywords: Alzheimer's disease; Amyloid β-protein; Dimer; Neurotoxicity; Oligomer