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Terminalia chebula Retz. (T.chebula) is an important medicinal plant in Tibetan medicine and Ayurveda. T.chebula is known as the "King of Tibetan Medicine", due to its widespread clinical pharmacological activity such as anti-inflammatory, antioxidative, antidiabetic as well as anticancer in lots of in vivo and in vitro models. In this study, we use transgenic and/or RNAi Caenorhabditis elegans (C.elegans) model to simulation the AD pathological features induced by Aβ, to detect the effect of TWE on improving Aβ-induced toxicity and the corresponding molecular mechanism. The study aimed to tested the activities and its possible mechanism of T.chebula to against Aβ 1-42 induced toxicity and Aβ 1-42 aggregation. Using transgenic C.elegans strain CL2006 and CL4176 as models respond to paralytic induced by Aβ toxicity. The transcription factors DAF-16 and SKN-1 were analyzed used a fluorescence microscope in transgenic strains (DAF-16:GFP, SKN-1:GFP). The function of DAF-16 and SKN-1 was further investigated using loss-of-function strains by feeding RNA interference (RNAi) bacteria. To evaluate the aggregation level of Aβ in the transgenic C.elegans , Thioflavin S (ThS) staining and WB visualized the levels of Aβ monomers and oligomers. TWE treatment can significantly improve the paralysis of transgenic C.elegans caused by Aβ aggregation (up to 14%). The Aβ aggregates in transgenic C.elegans are significantly inhibited under TWE exposure (up to 70%). TWE increases the nuclear localization of the key transcription factor DAF-16 and HSF-1, which in turn leads to the expression of downstream Hsp-16.2 protein and exerts its inhibitory effect on Aβ aggregation. Meanwhile, paralysis improved has not observed in SKN-1 mutation and/or RNAi C.elegans. Our results indicate that TWE can protect C.elegans against the Aβ 1-42 -induced toxicity, inhibition Aβ 1-42 aggregation and delaying Aβ-induced paralysis. The neuroprotective effect of TWE involves the activation of DAF-16/HSF-1/Hsp-16.2 pathway. Image 1 • The T.chebula water extract (TWE) can delay the paralysis induced by Aβ in transgenic and/or RNA interference C.elegans. • TWE shares protective function via reducing the production of Aβ oligomers. • TWE plays better effect of delaying Aβ-induced paralysis than the ethanol extract. • TWE has the physiological function of cognitive improvement. [ABSTRACT FROM AUTHOR]