Oxoisoaporphine alkaloid derivative 8-1 reduces Aβ1-42 secretion and toxicity in human cell and Caenorhabditis elegans models of Alzheimer's disease

• Published in: Neurochemistry international Vol. 108; pp. 157 - 168
• Main Authors: Huang, Liyingzi, Luo, Yunfeng, Pu, Zhijun, Kong, Xianghui, Fu, Xiang, Xing, Huanhuan, Wei, Shenqi, Chen, Wei, Tang, Huang
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.09.2017
• Subjects: Alzheimer's disease; Aβ1-42; Caenorhabditis elegans; Oxoisoaporphine alkaloid derivative; SH-SY5Y cell; Caenorhabditis elegans; Alzheimer's disease; Oxoisoaporphine alkaloid derivative; SH-SY5Y cell; Aβ1-42
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2017.03.007

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and a growing health problem worldwide. Because the drugs currently used to treat AD have certain drawbacks such as single targeting, there is a need to develop novel multi-target compounds, among which oxoisoaporphine alkaloid derivatives are promising candidates. In this study, the possible anti-AD activities of 14 novel oxoisoaporphine alkaloid derivatives that we synthesized were screened and evaluated. We found that, in the 14 novel derivatives, compound 8-1 significantly reduced Aβ1-42 secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found that compound 8-1 could down-regulate the expression level of β-amyloid precursor protein (APP) in APPsw cells. Moreover, compound 8-1 significantly delayed paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101, which could be explained by the fact that compound 8-1 down-regulated acetylcholinesterase activity, protected against H2O2-induced acute oxidative stress and paraquat-induced chronic oxidative stress, and enhanced autophagy activity. Taken together, our data suggest that compound 8-1 could attenuate the onset and development of AD. •Compound 8-1 reduced secreted Aβ1-42 level in APPsw cells which were SH-SY5Y cells overexpressing human β-amyloid precursor protein (APP).•Compound 8-1 delayed the paralysis in Aβ1-42-transgenic C. elegans GMC101.•Compound 8-1 could significantly protect Aβworms GMC101 against H2O2-induced acute oxidative stress and paraquat-induced chronic oxidative stress.•Compound 8-1 reduced AChE activity in Aβ1-42-transgenic C. elegans GMC101.•Compound 8-1 enhanced autophagy initiation gene bec-1 expression in GMC101 and could reduce autophagy substrate protein SQST-1 in BC12921.