Inhibition of Abeta Proteotoxicity by Paeoniflorin in Caenorhabditis elegans Through Regulation of Oxidative and Heat Shock Stress Responses

摘要

Alzheimer's disease (AD) is a common form of dementia and amyloid- peptide (A) aggregation is considered to be one of its main causes. Paeoniflorin has been previously shown to attenuate cognitive damage inflicted by exogenous A protein. Using transgenic Caenorhabditis elegans models expressing human A(1-42), we demonstrate here that paeoniflorin can delay progressive paralysis caused by endogenous A expression and reduce the amount of toxic A oligomers in vivo, although it has no effect on A aggregation in vitro. Paeoniflorin does not, however, affect the lifespan of either wild-type or AD-like nematodes, implying a mechanism independent of a general antiaging effect. We then demonstrate that paeoniflorin can reduce reactive oxygen species levels in C. elegans AD models, which may contribute to its in vivo suppression of A toxicity. Moreover, paeoniflorin is shown to upregulate the expression of the small heat shock protein HSP-16.2 as it is capable of increasing the hsp-16.2 transcript level in wild-type as well as AD-like nematodes and enhancing the fluorescence intensity in hsp-16.2::GFP nematodes. Taken together, our findings demonstrate the underlying mechanisms of the protective effect of paeoniflorin against age-onset A proteotoxicity, which are, in part, connected with oxidative and heat shock stress responses.