期刊
CHEMBIOCHEM
卷 23, 期 8, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202200029
关键词
Alzheimer's disease; amyloid-beta; disulfide bonds; oligomers; toxic conformations
资金
- JSPS KAKENHI [19H00921]
- Grants-in-Aid for Scientific Research [19H00921] Funding Source: KAKEN
Amyloid beta (A beta) oligomers play a critical role in Alzheimer's disease. The toxic conformation of A beta 42, rather than the oligomeric state, is essential for inducing cytotoxicity. Optimal compounds with potent cytotoxicity as toxic conformer models have been synthesized.
Amyloid beta (A beta) oligomers play a critical role in the pathology of Alzheimer's disease. Recently, we reported that a conformation-restricted A beta 42 with an intramolecular disulfide bond through cysteine residues at positions 17/28 formed stable oligomers with potent cytotoxicity. To further optimize this compound as a toxic conformer model, we synthesized three analogues with a combination of cysteine and homocysteine at positions 17/28. The analogues with Cys-Cys, Cys-homoCys, or homoCys-Cys, but not the homoCys-homoCys analogue, exhibited potent cytotoxicity against SH-SY5Y and THP-1 cells even at 10 nM. In contrast, the cytotoxicity of conformation-restricted analogues at positions 16/29 or 18/27 was significantly weaker than that of wild-type A beta 42. Furthermore, thioflavin-T assay, non-denaturing gel electrophoresis, and morphological studies suggested that the majority of these conformation-restricted analogues exists in an oligomeric state in cell culture medium, indicating that the toxic conformation of A beta 42, rather than the oligomeric state, is essential to induce cytotoxicity.
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