Efficacy and Mechanism of Schisandra chinensis Fructus Water Extract in Alzheimer’s Disease: Insights from Network Pharmacology and Validation in an Amyloid-β Infused Animal Model

Background/Objectives: Schisandra chinensis Fructus (SCF) is a traditional medicinal herb containing lignans that improves glucose metabolism by mitigating insulin resistance. We aimed to investigate the therapeutic potential and action mechanism of SCF for Alzheimer’s disease (AD) using a network pharmacology analysis, followed by experimental validation in an AD rat model. Methods: The biological activities of SCF’s bioactive compounds were assessed through a network pharmacology analysis. An AD rat model was generated by infusing amyloid-β peptide (Aβ) (25–35) into the hippocampus to induce Aβ accumulation. The AD rats were fed either 0.5% dextrin (AD-Con) or 0.5% SCF (AD-SCF group) in a high-fat diet for seven weeks. The rats in the normal/control group received an Aβ (35–25) infusion (no Aβ deposition) and were fed a control diet (Normal-C). Aβ deposition, memory function, inflammation, and glucose/lipid metabolism were evaluated. Results: The network analysis revealed significant intersections between AD-related targets and bioactive SCF compounds, like gomisin A, schisandrin, and longikaurin A. Key AD genes prostaglandin-endoperoxide synthase-2 (PTGS2, cyclooxygenase-2) and acetylcholinesterase (AChE) were linked to SCF compounds. In the rats with AD induced by bilaterally infusing amyloid-β (25–35) into the hippocampus, the 0.5% SCF intake mitigated hippocampal amyloid-β deposition, neuroinflammation, memory deficits, and dysregulated glucose and lipid metabolism versus the AD controls. SCF reduced hippocampal AChE activity, inflammatory cytokine expression related to PTGS2, and malondialdehyde contents and preserved neuronal cell survival-related factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor similar to normal rats. The neuroprotective effects validated the network analysis findings. Conclusions: SCF could be a potential AD therapeutic agent by activating the parasympathetic nervous system to reduce hippocampal oxidative stress and inflammation, warranting further clinical investigations of its efficacy.