Effect of the Nrf2/ARE signaling pathway on cognitive function and neuroinflammation in senescence accelerated mice
XU Yuzhu
BU Wei
YANG Ling
Abstract：Objective To explore the impact of the nuclear factor E2-related factor 2(Nrf2)/antioxidant response element(ARE)signaling pathway on cognitive function and neuroinflammation in the Senescence Accelerated Mouse-Prone 8(SAMP8)mice.Methods Male Senescence Accelerated Mouse Resistant 1(SAMR1)and SAMP8 mice with 4 months old were selected.SAMR1 or SAMP8 mice were injected with lentivirus-mediated Nrf2-ShRNA in the hippocampus to down-regulate Nrf2,or negative control(GFP),with 10 mice per group.The cognitive ability of mice was tested by novel object recognition test,water maze experiment and light-dark box test.Positive expressions of microtubule-associated protein 2(MAP2)and target gene Nrf2 in the hippocampus were observed by immunofluorescence staining.Western blot was used to examine protein levels of Nrf2,interleukin 6(IL-6),and tumour necrosis factor alpha(TNF-α)in the hippocampus.Results The novel object recognition experiment data showed a worse ability to discriminate novel objects in 9-month-old SAMP8 mice than age-matched SAMR1 mice(P＜0.05).No significant difference in the 1-h recognition index between SAMP8 mice transfected with Nrf2-ShRNA or GFP(P＞0.05).Recognition index at 24 h of delayed memory was significantly lower in SAMP8 mice transfected with Nrf2-ShRNA than those transfected with GFP(P＜0.05).The results of the Morris water maze test showed that the escape latency was significantly longer in SAMP8 mice than age-matched SAMR1 mice(P＜0.05),while no significant difference in the escape latency was detected in SAMR1 mice transfected with Nrf2-ShRNA or GFP(P＞0.05).In the spatial exploration experiment,the number of traveling across the platform was significantly less in SAMP8 mice than age-matched SAMR1 mice,which was much less in SAMP8 mice transfected with Nrf2-ShRNA than those transfected with GFP(P＜0.05),while no significant difference in the number of traveling across the platform was detected in SAMR1 mice transfected with Nrf2-ShRNA or GFP(P＞0.05).In the light-dark box test,9-month SAMP8 mice had significantly increased shock times compared to age-matched SAMR1 mice,and the shock times were significantly higher in SAMP8 mice transfected with Nrf2-ShRNA than those transfected with GFP,with a moderate downward trend for the escape latency(P＜0.05).The positive staining of MAP2 in the hippocampus was significantly less in SAMP8 mice compared to SAMR1 mice(P＜0.05).Compared with SAMP8 mice transfected with GFP,those transfected with Nrf2 shRNA had significantly less fluorescence intensity and positive staining of MAP2 in the CA3 region of the hippocampus(P＜0.05).Western blot showed significantly higher protein levels of IL-6 and TNF-αin the hippocampus of SAMP8 mice compared with the SAMR1 mice(P＜0.05).Their protein levels were significantly higher in SAMP8 mice transfected with Nrf2 shRNA than those transfected with GFP(P＜0.05).Conclusion Knockdown of Nrf2 disrupts MAP2-dependent neuronal structural integrity in SAMP8 mice,aggravates inflammation by upregulating inflammation factors like TNF-α and IL-6,and influences the cognitive function,suggesting that Nrf2 expression in the hippocampus is a key factor affecting cognitive function.
Keywords：nuclear factor E2-related factor 2(Nrf2)/antioxidant response element(ARE)signaling pathwayalzheimer diseaseinflammatory factorcognitive function
Publication Date：2024-11-10
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：7( 3205-3211 )