Oxoisoaporphine Alkaloid Derivative 8-1 Reduces Aβ1-42 Secretion And Toxicity In Human Cell And Caenorhabditis Elegans Models Of Alzheimer’s Disease

Objective: To study the effects of Oxoisoaporphine alkaloid derivative 8-1 in human cell and Caenorhabditis elegans models of Alzheimer’s disease and its possible mechanism and in provide preliminary research base for new drugs to attenuate onset and development of AD. Methods: Treat SH-SY5 Y cells with compound 8-1 solution, the concentration were(0.1, 0.5, 1, 5, 10, 20μM) respectively. MTT assay was done to detect cell viabilities after treatments. Aβ1-42 secretion level was tested by ELISA assay. Western blot was used to detect APP protein expression. The Aβ1-42-transgenic Caenorhabditis elegans strain GMC101 were randomly assigned into four groups(n=30 per group): control group, Oxoisoaporphine-Lipoic Acid hybrids administrated groups(0.1, 1, 10μM). So is the wild worm stain N2. Observe the following indicators:(1) paralysis rate;(2) lifespan;(3) the ability of Oxidative stress resistance(n=100 per group). The levels of relative ace-1and Aβ expression in worms were assayed by RT-PCR and calculated by the 2- Δ Δ Ct method. Measurements of AChE levels in worms using 5,5’-dithiobis(2-nitrobenzoic acid). The autophagy activity in worms was tested by fluorescence intensity measurement. Results: In this study, the possible anti-AD activities and action mechanisms of 14 novel oxoisoaporphine alkaloid derivatives synthesized by us were screened and evaluated. We found that, in the 14 novel derivatives, compound 8-1 showed excellent and reduced Aβ1-42 secretion in SH-SY5 Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein(APPsw). Next, we found compound 8-1 can down-regulate 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 that compound 8-1 could down-regulate acetylcholinesterase(AChE) activity and enhance autophagy activity. Conclusions: In sum, our data suggest that compound 8-1 could contribute to the lower pathogenesis of AD. Our findings support that compound 8-1 may be a novel potential compound to attenuate onset and development of AD.