Salidroside Alleviates AlCl 3 /D‐galactose‐Induced Alzheimer's Disease‐Like Mice Neuronal Damage and Synaptic Dysfunction Through Keap1/Nrf2/ GSH Signaling Axis

ABSTRACT Alzheimer's disease (AD) is associated with glutathione (GSH) depletion and redox imbalance in the brain, contributing to hippocampal neuronal damage and synaptic dysfunction and ultimately impairing learning and memory. Salidroside (Sal), the principal active component of Rhodiola rosea L ., exhibits antioxidant, anti‐inflammatory, and neuroprotective properties; however, its mechanisms of action in AD remain unclear. In this study, an AD‐like model was established in C57BL/6 mice using AlCl 3 /D‐galactose. The mice were subsequently treated with normal saline, Sal, or donepezil. A glutamate‐induced HT22 cell injury model was established, with ML385 (an inhibitor of Nrf2) used for functional validation. The underlying mechanisms were investigated using behavioral tests, hippocampal histopathological staining, western blotting, immunofluorescence, transmission electron microscopy, Golgi staining, metabolomics, network pharmacology, and molecular docking. Sal significantly improved learning and memory in AD‐like mice; reduced hippocampal β‐amyloid immunofluorescence, neuronal damage, and brain atrophy; inhibited microglial activation and inflammatory factor release; and attenuated oxidative stress. It also restored synaptic structure and increased the expression of synapse‐associated proteins. Metabolomic analysis revealed that Sal ameliorated disturbances in hippocampal GSH metabolism. Sal increased the expression of GSH metabolism‐related enzymes, upregulated glutamate‐cysteine ligase catalytic subunit and glutamate‐cysteine ligase modifier subunit, reduced Keap1 expression, and promoted nuclear Nrf2 accumulation. In summary, Sal attenuated oxidative stress and neuroinflammation and reduced neuronal and synaptic damage in AD‐like mouse brains. These effects were associated with alterations in hippocampal GSH metabolism and Keap1/Nrf2/GSH axis activation.