Therapeutical Effect Of Ginsenoside Composition In AD C. Elegans And Its Mechanisms

Alzheimer's disease is the first most prevalent neurodegenerative disease in the world.However,there is a lack of effective anti-AD drugs.Previous work showed that several kinds of ginsenosides have anti-AD activities.In present work,the therapeutic effects of 11 ginsenosides were evaluated by using AD C.elegans,and the ingredients and proportions of ginsenosides in the ginsenoside composition were also explored.Among them,a kind of preferred ginsenoside composition was obtained to have more of anti-AD activity,and its underlying mechanism was further investigated.The results showed that the ginsenoside composition Sum? had the optimal anti-AD activity on delaying AD-like pathological features of the paralysis phenotype induced by overexpression of A?_1-42 in worm muscle tissue.The ginsenoside composition Sum? contained 5.67%Rg1,21.59%Rb1,3.15%Rb3,10.36%Re,3.1%Rf,16.03%Rb2,26.67%Rc and 13.41%Rd.Further,Sum? has been demonstrated that it could also significantly attenuate AD-like symptom of hypersentivity to exogenous 5-HT,which was aroused by the overexpression of A?_1-42 in pan-neuron in worms.Similarly,Sum? significantly inhibited AD-like symptom of progressive muscle paralysis due to the constitutive expression of A?_1-42 in worm muscle tissue.Sum? has been showed that it significantly suppressed the abnormal deposition of A?in AD worms through ThS staining method,and decreased the levels of A?monomers and oligomers in AD worms by Western blot assay.After knocking down the expression of hsf-1,skn-1,cep-1 and daf-16 genes in AD worms by RNAi,the inhibitory effect of Sum? on worm paralysis phenotype was significantly partially cancelled only by hsf-1 RNAi,suggesting that Sum? was partially dependent on hsf-1to exert its anti-AD activity.Nonsense mutantion in hsf-1 was introduced to AD worms to generated animals with double phyenotype of paralysis and inactivation of hsf-1.After treatment with Sum?,similar result was obtained.Western blot analysis showed that Sum? could not decrease the level of A?oligomers any more after hsf-1 RNAi.In addition,Sum? could significantly promote the expression of the hsp-16.2 gene downstream of HSF-1.Meanwhile,Sum? did not affect the expression of normal protein GFP,which was used as transfer genetic control of abnormal A?in worms.These results suggested that Sum? was partially dependent on the HSF-1 signaling pathway to inhibit A?oligomer level to exert an anti-AD effect.Our results will provide new clues for the rational development and utilization of ginseng extraction and ginsenosides.