Platycodin D Attenuates Behavioral Deficits, Amyloid-β Accumulation and Mitochondrial Impairment in AD Models by Inhibiting the cGAS-STING Pathway.

Abstract

The characteristics of Alzheimer's disease (AD) include behavioral deficits, amyloid-β (Aβ) accumulation, and mitochondrial impairment. Activating of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway significantly increases the production of inflammatory cytokines, which can exacerbate neuroinflammation and accelerate the progression of AD. Platycodin D (PD) has been reported to exhibit anti-inflammatory and neuroprotective properties and is believed to play a role in the progression of AD. Our study aimed to investigate the protective effects of PD in AD and to determine whether these protective effects are associated with the cGAS-STING pathway. In this research, APP/PS1 transgenic mice, an animal model of AD, were administered with PD via intracerebroventricular injection. SHSY5Y cells stably transfected with APPswe gene (APPswe cells) were used as a cell model of AD and treated with PD. Our findings demonstrated that PD attenuated behavioral deficits, Aβ accumulation, mitochondrial impairment, and decreased the expression level of cGAS-STING pathway proteins (cGAS and STING) as well as inflammatory cytokines (TNF-α, IL-1β and IL-18) in AD models. However, cGAMP acts as an agonist of the cGAS-STING pathway upregulated the cGAS-STING pathway and inflammatory cytokines, exacerbated Aβ accumulation and mitochondrial impairment in APPswe cells. In conclusion, our findings suggested that PD attenuated behavioral deficits, Aβ accumulation and mitochondrial impairment in AD models by inhibiting cGAS-STING pathway.