Affiliations 1 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P. R. China. 2 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P. R. China. Electronic address: houxueqin09@12com.
Alzheimer's disease represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol , a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain ...更多
Alzheimer's disease represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol , a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine , Choline acetyltransferase , Tyrosine kinase-A , and Nerve growth factor expression; downregulation of Acetylcholinesterase activity; and increased expression of Estradiol , Estrogen receptor-α , and Estrogen receptor-β . In addition, OST improved synaptic plasticity , Synuclein , and Brain-derived neurotrophic factor ), inhibited neuronal apoptosis and Bcl-2-associated X protein ), and enhanced neurotransmitter signaling cascades , Glutamic acid , Epinephrine , and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.收起
