Liu_2026_Neurochem.Int__106241

Alzheimer's disease (AD) 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 (OST), 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 3xTg-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 3xTg AD mice across different age groups. OST significantly improved learning and memory performance in 3xTg 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 (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-alpha (ERalpha), and Estrogen receptor-beta (ERbeta). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (gamma-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.