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Current therapeutic approaches for Alzheimer's disease (AD) demonstrate limited efficacy and fail to address disease progression. In the present study, we present HSN-G1, a novel ginsenoside-enriched pharmaceutical formulation that employs a dual-target mechanism through the modulation of amyloid clearance pathways and cholinergic neurotransmission. HSN-G1 demonstrates a reproducible ginsenoside profile enriched with Re (33.27 mg/g), Rd (25.00 mg/g), and Rg3 stereoisomers (12.18 mg/g), ensuring pharmaceutical-grade reproducibility. HSN-G1 enhanced amyloid-beta (Aβ) clearance in microglial cells, with significantly greater effects observed in SRA-overexpressing cells, suggesting SRA-dependent clearance mechanisms. In APP/PS1 transgenic mice, six-week oral administration of HSN-G1 (100-400 mg/kg) elicited significant dose-dependent improvements in cognitive performance. Male mice exhibited more stable and consistent enhancements in both passive avoidance and spatial memory tests compared to vehicle controls (p < 0.001), while both sexes demonstrated comparable reductions in brain Aβ levels (approximately 45%) and differential increases in acetylcholine (73% in males; 55% in females, p < 0.01). HSN-G1 administration enhanced the expression of neurotrophic factors, with NGF upregulation predominantly observed in males, whereas BDNF, CNTF, and GDNF were consistently elevated across both sexes. These findings establish HSN-G1 as a promising disease-modifying agent with standardized composition and therapeutic efficacy, surpassing the limitations of conventional single-target approaches. The superior efficacy of HSN-G1 compared to existing treatments validates its potential for clinical development, highlighting the significance of sex-specific therapeutic responses in future AD therapeutics. Show less

Alzheimer's disease (AD) and osteoporosis are common age-related degenerative diseases. Emerging evidence suggests that amyloid-β (Aβ) deposition may contribute to the pathogenesis of both conditions. This study investigated whether probucol could alleviate AD-associated bone loss and Aβ42-induced osteoblast dysfunction, and further explored the underlying mechanisms. Female mice were divided into four groups (n = 5 per group): C57BL/6 wild-type (WT), WT treated with probucol (WT + PBC), APP/PS1 transgenic (AD) mice, and AD treated with probucol (AD+PBC). Bone mineral density (BMD) was assessed by micro-CT. Levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) along with bone metabolism markers including fibroblast growth factor 23 (FGF23), sclerostin, and brain-derived neurotrophic factor (BDNF) in bone and brain tissues were measured by ELISA. FOXO3a was knocked down in the bone marrow of APP/PS1 mice via stereotactic injection of lentiviral vectors. Expression of APP and FOXO3a in bone tissue was evaluated using RT-qPCR and Western blotting (WB). Mitochondrial damage in osteoblasts and neuronal cells was assessed by transmission electron microscopy (TEM). In vitro study, osteoblast differentiation and mineralization deficits were evaluated using Alizarin Red staining. WB was used to measure the expression of AKT, FOXO3a, autophagy and apoptosis related proteins. Probucol attenuated bone loss and mitochondrial damage in both APP/PS1 and FOXO3a-knockdown APP/PS1 mice, and improved cognitive impairment and neuronal ultrastructure in APP/PS1 mice. Furthermore, probucol attenuated Aβ42-induced osteoblast differentiation and mineralization via the AKT/FOXO3a signaling pathway in vitro. These findings demonstrate that probucol ameliorates AD-associated bone loss and Aβ42-induced osteoblast impairments by regulating AKT/FOXO3a signaling pathway. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated Show less