Integrated identification and validation of HSP90AA1 as a therapeutic target of Astragalus membranaceus in Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder lacking effective disease-modifying therapies. Astragalus membranaceus (AM) has shown potential neuroprotective effects, but its underlying mechanisms remain incompletely understood. In this study, a meta-analysis, network pharmacology, molecular simulation, and experimental validation were integrated to investigate the therapeutic potential of AM in AD. Meta-analysis of three randomized controlled trials showed that AM significantly improved Clinical Dementia Rating-Sum of Boxes scores, whereas no significant differences were observed for MMSE, memory-related outcomes, or SNSB-D. Network pharmacology identified 350 overlapping targets between AM and AD, with enrichment in pathways related to PI3K-Akt signaling and neural ligand-receptor interactions. HSP90AA1, PIK3CA, and ESR1 were identified as hub targets. Molecular docking predicted stable binding of astragaloside VII to the ATP-binding pocket of HSP90AA1 (-8.9 kcal/mol), which was further supported by molecular dynamics simulation and MM/PBSA analysis (-63.13 ± 4.82 kcal/mol). In Aβ-induced SH-SY5Y cells, astragaloside VII improved cell viability, reduced inflammatory cytokine production and the Aβ42/Aβ40 ratio, restored mitochondrial membrane potential, decreased reactive oxygen species accumulation, alleviated Tau hyperphosphorylation, and increased PSD95 expression. These effects were markedly attenuated following HSP90AA1 knockdown. Collectively, these findings suggest that AM may exert neuroprotective effects through HSP90AA1-associated regulation of multiple AD-related pathological processes and provide preliminary evidence supporting further mechanistic and translational studies.