[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].

This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.