Quercetin Ameliorates Learning and Memory in OVX/D-gal-Induced Alzheimer’s Disease in Rats by Inhibiting Neuroinflammation via cGAS-STING Signal Pathway

Alzheimer’s disease (AD) is an age-related degenerative disorder of the central nervous system. Neuroinflammation is considered a key factor in its etiology and progression. AD is more prevalent in women than men and may be related to postmenopausal hormone deficiency. This study constructed an AD rat model by bilateral ovariectomy (OVX) and intraperitoneal injection of D-galactose (D-gal) and an in vitro AD cell model was induced in PC12 cells using lipopolysaccharide (LPS). The Morris water maze test was employed to assess the impact of quercetin (Que) on learning and memory in OVX/D-gal rats. Immunohistochemistry was utilized to assess the impact of Que on the expression of Aβ protein, p-tau protein, GFAP, and Iba1 in the hippocampus of OVX/D-gal rats. Nissl staining was performed to examine hippocampal pathological damage. ELISA was conducted to measure serum estrogen levels and the release of inflammatory cytokines, specifically TNF-α and IL-1β, in the hippocampus of OVX/D-gal rats. HE staining was utilized to evaluate uterine pathological alterations in OVX/D-gal rats. Cell viability was assessed using the CCK-8 assay to determine the protective effect of quercetin on LPS-induced PC12 cells. Western Blot analysis was conducted to evaluate the expression levels of estrogen receptors and the proteins associated with the cGAS-STING pathway in both in vitro and in vivo models. Protein–protein docking studies were performed to investigate the binding affinity between the estrogen receptor and proteins involved in the cGAS-STING signaling pathway. Results demonstrated that Que enhanced learning and memory capabilities in OVX/D-gal rats, alleviated hippocampal pathological damage, reduced the expression of Aβ, p-tau, GFAP, and Iba1, and inhibited the release of inflammatory factors. Additionally, Que activated estrogen receptor expression and increased serum estrogen levels without exacerbating uterine lesions. Furthermore, Que activated the estrogen receptor in LPS-induced PC12 cells, which inhibited the release of IL-6 and exerted neuroprotective effects. Que also suppressed the expression of proteins associated with the cGAS-STING pathway both in vitro and in vivo. Estrogen receptors exhibited strong binding affinity with cGAS-STING pathway proteins. In conclusion, Que can inhibit neuroinflammation in vitro and in vivo, enhance learning and memory in OVX/D-gal rats, and exert neuroprotective effects. The underlying mechanism may involve the inhibition of the cGAS-STING signaling pathway, and the estrogen receptor potentially influences this pathway directly or indirectly.