Synthetic Models of Quasi-Stable Amyloid β40 Oligomers with Significant Neurotoxicity

被引:29
作者
Irie, Yumi [1 ]
Murakami, Kazuma [1 ]
Hanaki, Mizhuo [1 ]
Hanaki, Yusuke [1 ]
Suzuki, Takashi [1 ]
Monobe, Yoko [2 ]
Takai, Tomoyo [2 ]
Akagi, Ken-ichi [2 ]
Kawase, Taiji [3 ]
Hirose, Kenji [3 ]
Irie, Kazuhiro [1 ]
机构
[1] Kyoto Univ, Grad Sch Agr, Div Food Sci & Biotechnol, Kyoto 6068502, Japan
[2] Natl Inst Biomed Innovat Hlth & Nutr, Osaka 5670085, Japan
[3] Nihon Waters K K, Tokyo 1400001, Japan
关键词
Amyloid beta; beta-sheet; dimer; ion mobility-mass spectrometry; neurotoxicity; oligomer; SOLID-STATE NMR; ATOMIC-RESOLUTION STRUCTURE; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; SECONDARY STRUCTURE; FIBRIL FORMATION; TOXIC CONFORMER; PROTEIN; A-BETA-42; VERIFICATION;
D O I
10.1021/acschemneuro.6b00390
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The formation of soluble oligomers of amyloid beta 42 and 40 (A beta 42, A beta 40) 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 A beta 42, 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 A beta 42, A beta 40 dimers can also contribute to AD progression because of the more abundance of A beta 40 monomer in biological fluids. Here, we describe the synthesis and characterization of three dimer models of the toxic-conformation constrained E22P-A beta 40 using L,L-2,6-diaminopimeric acid (DAP) or L,L-2,8diaminoazelaic acid (DAZ) linker at position 30, which is incorporated into the intermolecular parallel beta-sheet region, and DAP at position 38 in the C-terminal hydrophobic core. E22P-A3ODAP-A beta 40 dimer (1) and E22P-A3ODAZ-A beta 40 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-A beta 40 dimer (3) formed beta-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 beta-sheet, triggers the formation of toxic A beta oligomers. Compound 3 may be a suitable model for studying the etiology of Alzheimer's disease.
引用
收藏
页码:807 / 816
页数:10
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