Yuan-zhi-san inhibits tau protein aggregation in an Aβ(1–40)-induced Alzheimer's disease rat model via the ubiquitin-proteasome system

Yuan-zhi-san (YZS) is a classic type of Traditional Chinese Medicine, which has been reported to aid in the treatment of Alzheimer's disease (AD). The present study aimed to investigate the effects of YZS on tau protein aggregation, a hallmark of AD pathology, and its possible mechanisms. The results demonstrated that YZS improved learning and memory abilities, and decreased the severity of AD pathology in β-amyloid (Aβ(1–40))-induced AD rats. Moreover, YZS administration inhibited the hyperphosphorylation of tau protein at Ser199 and Thr231 sites. Several vital enzymes in the ubiquitin-proteasome system (UPS), including ubiquitin-activating enzyme E1a/b, ubiquitin-conjugating enzyme E2a, carboxyl terminus of Hsc70-interacting protein, ubiquitin C-236 terminal hydrolase L1 and 26S proteasome, were all significantly downregulated in AD rats, which indicated an impaired enzymatic cascade in the UPS. In addition, it was identified that YZS treatment partly increased the expression levels of these enzymes in the brains of AD rats. In conclusion, the present results suggested that YZS could effectively suppress the hyperphosphorylation of tau proteins, which may be partially associated with its beneficial role in restoring functionality of the UPS.