Amelioration of early pathological changes in the 3xTg-AD mouse model: Mechanism of action of the Chinese herbal formula Tianqi Granules

Alzheimer’s disease is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline. This study investigated the effects of the Chinese herbal formula Tianqi Granules on early pathological progression in the 3xTg-AD mouse models and investigated the underlying mechanisms. After 31 days of Tianqi Granule treatment initiated at 5 months of age, Tianqi Granules-treated mice showed improved performance in the open-field test, novel object recognition test, and Morris water maze test. Amyloid deposition and glial activation were attenuated, and immunoreactivity for interleukin-1β and LC3 was reduced. Hippocampal transcriptome sequencing at multiple time points showed that, in untreated mice, early pathological progression occurred in three successive phases, with the dominant processes shifting from compensatory programs to failing homeostasis and subsequently to degenerative changes. Tianqi Granule treatment was associated with a three-phase response centered on the restoration of homeostasis and involving proteostasis, nuclear processes, lipid and carbohydrate metabolism, and redox-related pathways. Multiple biological domains were engaged rather than a single target. In males, an interferon-related program associated with Irf7 was induced early and shifted in the opposite direction under Tianqi Granule treatment during the same time window. Network pharmacology identified OPRK1 as the only candidate target shared by both sexes, making it a potential target for future investigation. These findings suggest that Tianqi Granule modulates the pathology of Alzheimer’s disease through coordinated actions on multiple targets and may influence systemic metabolic homeostasis, providing experimental support for early therapeutic intervention in Alzheimer’s disease.