Hesperetin Early Intervention Reduces Β-Amyloid Production in APP/PS1 Mice by Decreasing Beta and Gamma-Secretase Enzyme

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by β-amyloid (Aβ) plaque accumulation and cognitive decline. Early intervention targeting Aβ production may mitigate AD progression. This study investigated the neuroprotective effects of hesperetin, a citrus flavonoid, in APPswe/PS1dE9 transgenic mice. Methods: APPswe/PS1dE9 mice (3 months old) were administered hesperetin (20, 40, and 80 mg/ kg/day) for 6 months. Cognitive function was assessed using the Morris water maze and the Barnes maze. Neuronal morphology in the hippocampal CA1 region was examined using thionin staining. Aβ40, Aβ42, β-secretase, and γ-secretase levels in brain tissue and serum were measured by ELISA, and tau protein expression was analyzed by Western blotting. Results: Hesperetin-treated mice exhibited improved learning and memory, reduced neuronal degeneration, and lower tau expression. Brain tissue showed decreased Aβ40, Aβ42, and secretase levels, whereas serum Aβ levels increased, suggesting enhanced Aβ clearance. Discussion: Hesperetin may attenuate AD pathology by inhibiting β- and γ-secretase activity, reducing Aβ production, and promoting Aβ efflux to peripheral circulation. Conclusion: Early hesperetin intervention demonstrates potential as a therapeutic strategy for AD by modulating Aβ metabolism and preserving cognitive function.