Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive dysfunction. Kai-Xin-San (KXS) is a traditional Chinese medicine (TCM) formula that has been used to treat AD patients for over a thousand years in China. However, the therapeutic mechanisms of KXS for treating AD have not been fully explored. Herein, we used a comprehensive network pharmacology approach to investigate the mechanism of action of KXS in the treatment of AD. This approach consists of construction of multiple networks and Gene Ontology enrichment and pathway analyses. Furthermore, animal experiments were performed to validate the predicted molecular mechanisms obtained from the systems pharmacology-based analysis. As a result, 50 chemicals in KXS and 39 AD-associated proteins were identified as major active compounds and targets, respectively. The therapeutic mechanisms of KXS in treating AD were primarily related to the regulation of four pathology modules, including amyloid beta metabolism, tau protein hyperphosphorylation process, cholinergic dysfunction, and inflammation. In scopolamine-induced cognitive dysfunction mice, we validated the anti-inflammatory effects of KXS on AD by determining the levels of inflammation cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. We also found cholinergic system dysfunction amelioration of KXS is correlated with upregulation of the cholinergic receptor CHRNB2. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the underlying therapeutic mechanism of KXS for the treatment of AD.
Highlights
Alzheimer's disease (AD), as the most common form of dementia, has become one of the leading causes of morbidity and mortality in the aged population
Acetylcholinesterase inhibitors and NMDA receptor antagonists have been the primary choice for treating AD patients, showing marginal benefits for alleviating symptoms
It is urgent that novel and efficient curative remedies are discovered for AD patients
Summary
Alzheimer's disease (AD), as the most common form of dementia, has become one of the leading causes of morbidity and mortality in the aged population. According to the World Alzheimer Report, up to 2019, there were over 50 million people living with dementia (Cao et al, 2018b; Gaugler and Al, 2019). Patients with AD suffer from a decline in learning and memory, cognitive deficits, and behavioral/personality changes, which lead to a heavy public health burden (Jia et al, 2018; Kumar and Tsao, 2019). Current treatments can only provide limited symptomatic-relief benefits but fail to stop or reverse disease progression. Adverse effects, including diarrhea, nausea, and nightmares, further restrict the clinical treatment of AD (Masters et al, 2015). There is an urgent need to discover novel therapeutic drugs with new mechanisms of action (MOAs) for treating AD
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