Identification of Key Pathways and Targets of Kai Xin San in The Treatment of Alzheimer's Disease Based On a Network Pharmacology Approach and Experimental Validation

Abstract

Background: Alzheimer's disease (AD) is the commonest neurodegenerative disease characterized with a progressive loss of cognitive functions and memory decline. Kai Xin San (KXS), a traditional Chinese herbal classic prescription, has been used to ameliorate cognitive dysfunction for thousands of years. However, its specific pharmacological molecular mechanisms have not been fully clarified.Methods: The ingredients of KXS and their corresponding targets were firstly screened from ETCM database. AD-related target proteins were obtained from Malacards database and DisGeNet database. Venn diagram was used to intersect the common targets between KXS and AD. Then, key ingredients and key targets were identified from compound-target-disease network and protein-protein interaction (PPI) network analysis respectively. Moreover, the binding affinity between the key ingredients and targets were verified by molecular docking. KEGG enrichment analysis further predicted the potential key signaling pathway involved in the treatment of KXS on AD, and the predicted signaling pathway was validated via experimental approach.Results: A total of 38 ingredients and 469 corresponding targets were screened, and 264 target proteins associated with AD were obtained. Compound-target-disease network and PPI identified the key active ingredients and targets, which correlate with the treatment of KXS on AD. Molecular docking revealed a good binding affinity between key ingredients and targets. KEGG pathway analysis suggested the potential effect of KXS in treatment of AD via Aβ-GSK3β-Tau pathway. Aβ1-42-injected induced a decline in spatial learning and memory and upregulated the expression of GSK3β and CDK5 along with the downregulated PP1 and PP2 expression. However, KXS significantly improve the cognitive deficits induced by Aβ1-42, decrease the GSK3β and CDK5 levels and increase the expression of PP1 and PP2.Conclusions: Our research elucidated that KXS exerted neuroprotective effects through regulating the Aβ-GSK3β-Tau signaling pathway, which provided a novel insight into the therapeutic mechanism of KXS in treatment of AD.

Network pharmacology implicates traditional Chinese medicine in regulating systemic homeostasis to benefit Alzheimer’s disease

“…KXS targets disclosed in preprint data by Yang et al . [ 67 ] (Preprint, https://doi.org/10.21203/rs.3.rs-966634/v1) are used to discover the intersection of genes associated with AD and metabolic disorders [ Figure 3 ]. Vann diagrams show that 17 diabetes, 13 hypertension, and 5 atherosclerosis-related KXS targets overlap with AD-related genes, respectively.…”