Protective Effects Of 5-heptadecylresorcinol On Cognitive Impairments In APP/PS1 Transgenic Mice

Alzheimer’s disease(AD)is one of the most common progressive neurodegenerative disorder,which incidence exponential rises with trend of population aging.Because the molecular mechanism of AD is still unknown,there are no drugs to effectively cure AD in the world.In recent years,people pay great attention to the prevention and control of AD by means of lifestyle adjustment and nutrition intervention.Prospective population-based cohort study showed that whole grain food could effectively prevent and control the occurrence and development of Alzheimer’s disease,but the specific mechanism is still not clear.As an important functional active ingredient in the whole grains and one of the biomarkers for eating whole wheat food,5-heptadecyl resorcinol(AR-C17)has been proved to have many physiological functions,such as anti-inflammatory,anti-oxidation and anti-tumor.Therefore,the objective of this study is to explore the protective effects of AR-C17 on the cognitive dysfunction of APPswe/PSEN1 d E9(APP/PS1)transgenic mice with Alzheimer’s disease,and to provide a theoretical basis for better promotion of whole grain food.In this study,Morris water maze test was used to evaluate the effect of AR-C17 on cognitive impairment of APP / PS1 double transgenic mice.The results showed that oral administration of AR-C17(150mg/kg/d)for 5 months could significantly improve the memory impairment and learning ability of APP / PS1 transgenic mice.Furthermore,immunohistochemistry and Western blotting were used to detect the pathological sections and related proteins in the cerebral cortex and hippocampus of mice brain.The results showed that AR-C17 could significantly reduce the aggregation of Aβ plaque and the hyperphosphorylation of Tau protein in both cortex and hippocampus of mice,and enhance the expression of ADAM10,Postsynaptic density protein 95(PSD 95)and synaptophysin(SYP)meanwhile.In addition,AR-C17 can reduce the production of Cysteinyl aspartate specific proteinase(caspase-1)and Interleukin-1β(IL-1β)mediated by NLRP3 by inhibiting the activation of microglia and astrocytes.The analysis of 16 S r RNA gene sequencing of mice feces showed that AR-C17 intervention ameliorated the intestinal dysbacteriosis of AD mice,significantly increased the relative abundance of Akkermansia and Lactobacillus and reduced the relative abundance of Clostridium and Desulfovibrio.The upstream pathway analysis showed that AR-C17 significantly increased the expression of Sirtuin3(SIRT3)signaling pathway in AD mice brain.Combined with the cell experiments in vitro,AR-C17 intervention significantly activated the expression of SIRT3 and its downstream protein Forkhead box O3(FOXO3a),which alleviate the oxidative damage and apoptosis of neurons and maintain the oxidative respiratory function of mitochondria meanwhile.However,the protective effects of AR-C17 on neurons could be reversed by SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine(3-TYP).Therefore,AR-C17 could improve the cognitive impairment of APP/PS1 double transgenic mice by regulating SIRT3 signaling pathway.