Depichering the Effects of Astragaloside IV on AD-Like Phenotypes: A Systematic and Experimental Investigation

Astragaloside IV (AS-IV) is an active component in Astragalus membranaceus with the potential to treat neurodegenerative diseases, especially Alzheimer's diseases (ADs). However, its mechanisms are still not known. Herein, we aimed to explore the systematic pharmacological mechanism of AS-IV for treating AD. Drug prediction, network pharmacology, and functional bioinformatics analyses were conducted. Molecular docking was applied to validate reliability of the interactions and binding affinities between AS-IV and related targets. Finally, experimental verification was carried out in A beta O infusion produced AD-like phenotypes to investigate the molecular mechanisms. We found that AS-IV works through a multitarget synergistic mechanism, including inflammation, nervous system, cell proliferation, apoptosis, pyroptosis, calcium ion, and steroid. AS-IV highly interacted with PPAR gamma, caspase-1, GSK3 Beta, PSEN1, and TRPV1 after docking simulations. Meanwhile, PPAR gamma interacts with caspase-1, GSK3 Beta, PSEN1, and TRPV1. In vivo experiments showed that A beta O infusion produced AD-like phenotypes in mice, including impairment of fear memory, neuronal loss, tau hyperphosphorylation, neuroinflammation, and synaptic deficits in the hippocampus. Especially, the expression of PPAR gamma, as well as BDNF, was also reduced in the hippocampus of AD-like mice. Conversely, AS-IV improved A beta O infusion-induced memory impairment, inhibited neuronal loss and the phosphorylation of tau, and prevented the synaptic deficits. AS-IV prevented A beta O infusion-induced reduction of PPAR gamma and BDNF. Moreover, the inhibition of PPAR gamma attenuated the effects of AS-IV on BDNF, neuroflammation, and pyroptosis in AD-like mice. Taken together, AS-IV could prevent AD-like phenotypes and reduce tau hyperphosphorylation, synaptic deficits, neuroinflammation, and pyroptosis, possibly via regulating PPAR gamma.

Automated summary

The study demonstrated that AS-IV exerts its effects in treating Alzheimer's disease through a multitarget synergistic mechanism involving various pathways such as inflammation, nervous system, cell proliferation, and apoptosis. In vivo experiments showed that AS-IV can prevent AD-like phenotypes, reduce tau hyperphosphorylation, and improve synaptic deficits, possibly by regulating PPAR gamma.