Huannao Yicong decoction ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by interfering with neurotoxic interaction of A-tau

Ethnopharmacological relevance: Huannao Yicong decoction (HYD) has been used in the study of AD for many years, which consists of Polygonum multiflorum Thunb., Panax ginseng C.A.Mey., Acorus gramineus Aiton, Coptis chinensis Franch., and Conioselinum acuminatum (Franch.) Lavrova. Previous studies have found that HYD could reduce ss-Amyloid (A ss) deposition and tau hyperphosphorylation which are the two critical pathological factors of AD. However, the mechanism of the neurotoxic interaction between A ss and tau in AD remains unclear. Thus, the underlying mechanisms for HYD improving cognitive function of AD by interfering with the neurotoxic interaction between A ss and tau remain to be explored. Aim of the study: The main objective of this study is to clarify the specific mechanisms of HYD on interfering with the neurotoxic interaction between A ss and tau of AD both in vivo and in vitro. Materials and methods: APP/PS1/tau triple transgenic mice were randomly divided into 4 groups, namely model group, memantine group, HYD low-dose group (HYD-L), and HYD high-dose group (HYD-H) with 28 mice in each group, while 28 C57BL/6J mice as the control group. Gavage was applied to all the mice daily for 24 weeks. SH-SY5Y model cells overexpressing A ss and tau proteins as the intervention object in vitro experiments. Morris water maze was used to observe the learning and memory ability of APP/PS1/tau mice. A ss deposition was detected by immunohistochemistry, and the levels of A ss 1- 40 and A ss 1- 42 were detected by enzyme-linked immunosorbent assay (ELISA). Neurofibrillary tangles (NFTs) were observed by silver staining and the levels of phosphorylated tau proteins were detected by Western blot. The GSK-3 ss and CDK-5 mRNA expression were detected by real-time polymerase chain reaction (RT-PCR). Besides, the levels of PSD95, GluR1, NR2A, and NR2B were detected by Western blot. Meanwhile, cell experiments were performed to further verify the effect of HYD on tau phosphorylation related kinases (GSK-3 ss, CDK-5, and PP2A), which further to clarify the mechanism of HYD intervention on the neurotoxic interaction between A ss and tau. Results: HYD improved the learning and memory ability of APP/PS1/tau mice. HYD decreased the levels of A ss 1- 40 and A ss 1- 42 and inhibited tau hyperphosphorylation, which reduced A ss deposition and NFTs forming. In addition, HYD inhibited the activity of kinases GSK-3 ss and CDK-5, and enhancing the activity of kinase PP2A. Moreover, HYD inhibited the overexpression of NR2A and NR2B, and increased the expression of GluR1 and postsynaptic density protein-95 (PSD95). Conclusions: HYD can improve the cognitive deficits by interfering with the neurotoxic interaction between A ss and tau. In addition, HYD can inhibit the overactivation of NMDARs and increase the levels of GluR1 and PSD95, which may play a role in alleviating neuronal excitotoxicity and improving synaptic function.