Salidroside mitigates cognitive deficits in AlCl3 exposed aging mouse by modulating APP processing and mitochondrial dysfunction

Background and objectivesMitochondrial dysfunction and oxidative stress are key contributors to the progression of Alzheimer’s disease (AD). Salidroside, a bioactive glycoside derived from Rhodiola rosea, exhibits neuroprotective and antioxidative properties; however, its effects on mitochondrial dysfunction and APP processing in AD remain to be fully elucidated.Methods and study designWe employed both in vivo and in vitro models to evaluate the neuroprotective potential of salidroside. D-galactose-induced AlCl3 exposed aging mouse model was used for behavioral assessments, biochemical analyses of brain tissue biomarkers, and evaluation of mitochondrial dysfunction-related proteins and functions. In vitro experiments with HT-22 hippocampal neurons assessed the effects of salidroside on oxidative stress, mitochondrial integrity, apoptosis, and amyloid precursor protein (APP) processing.ResultsSalidroside significantly improved cognitive performance and reduced Aβ deposition in the AlCl3 exposed aging mouse by modulating APP processing, characterized by downregulation of β- and γ-secretase activities and enhancement of α-secretase activity. These changes coincided with decreased mitochondrial protein aggregation and restored mitochondrial function and redox balance. In vitro, salidroside attenuated reactive oxygen species (ROS) generation, inhibited neuronal apoptosis, and suppressed Aβ production, demonstrating broad neuroprotective effects relevant to AD pathology.ConclusionOur results suggest that salidroside may alleviate mitochondrial dysfunction and reduce mitochondrial protein aggregation by modulating APP processing, promoting sAPPα production while decreasing β-CTF and Aβ levels. These findings provide preliminary evidence supporting the neuroprotective potential of salidroside in ameliorating mitochondrial impairment and cognitive deficits associated with Alzheimer’s disease, warranting further investigation.