Objective To explore the effect of different doses of hesperetin early intervention on β-amyloid transporter in APPswe/PS1dE9 transgenic mice. Methods The 3-month-old C57BL/6J wild type mice were set up as the control group, the 3-month-old APPswe/PS1d E9 transgenic mice were randomly divided into the model group, hesperetin low-dose group, medium-dose group and high-dose groups (20, 40, 80 mg·kg ^-1·d ^-1), and gavage once a day for 6 months. Immunohistochemistry was applied to test the expression of insulin-degrading enzyme (IDE) in brain tissue, Western blotting (WB) was applied to detect receptor of advanced glycation endproducts (RAGE), low density lipoprotein receptor-associated protein 1 (LRP-1) , P-glycoprotein (P-gp) and the blood-brain barrier related proteins Claudin-5, Occludin and occlusive zonolin-1 (ZO-1). Results Compared with the model group, IDE expression was significantly enhanced in three hesperetin groups. Compared with the control group, the model group exhibited decreased expressions of P-gp and LRP-1, increased expression of RAGE, and decreased expressions of Claudin-5, Occludin, and ZO-1. In contrast, compared with the model group, the hesperetin groups showed increased expressions of P-gp and LRP-1, decreased expression of RAGE, and increased expressions of Claudin-5, Occludin, and ZO-1(P<0.05). Conclusion Early intervention of hesperetin in APPswe/PS1dE9 mice can affect Aβ metabolismand transport by enhancing IDE activity, regulating Aβ transporter and blood-brain barrier tightness.

Objective To explore the effect of hesperetin early intervention to astrocyte in wild type and APPswe/PS1dE9 double transgenic mice. Methods The 3-month-old C57BL/6J wild type mice were set up as control group, hesperetin 10 mg/kg/d and 20 mg/kg/d group. The 3-month-old APPswe/PS1dE9 transgenic mice were set up as model group, hesperetin 20 mg/kg/d, 40 mg/kg/d, and 80 mg/kg/d groups, continuous intragastric administration for 6 months, once a day. The mice were killed after 6 months of intragastric administration, and 3-month-old C57BL/6J mice were purchased as normal control group. Immunohistochemical was used to test the expression of GFAP in mouse brain, double immunofluorescence staining was used to test the co-localized expressions of GFAP/C3 and GFAP/S100A10, Western Blot was used to observe the expression of GFAP and C3 in brain tissues of mice, IL-1α and TGF-β1 in brain tissue of mice were tested by using ELISA. Results Compared with the normal control group, the expression of GFAP and C3 in the control group increased, the number of GFAP/C3 colocalization positive cells increased, while the GFAP/S100A10 decreased. Compared with the control group, hesperetin could decrease the expression of GFAP, the number of GFAP/C3 colocation-positive cells, C3 as well as IL-1α, while the number of GFAP/S100A10 positive cells, TGF-β1 increased. Compared with the control group, the expression of GFAP, C3 in the model group increased, while the number of GFAP/S100A10 positive cells decreased. Compared with the model group, the expression of GFAP, C3 and the number of GFAP/C3 colocation-positive cells in hesperetin group decreased, while the expression of TGF-β1 and the number of GFAP/S100A10 colocation-positive cells increased (P<0.05). Conclusion Hesperetin early intervention can significantly alleviate the inflammation of naturally aged mice and transgenic mice, and its mechanism may be related to inhibiting the activation of astrocytes, promoting the activation of anti-inflammatory A2 cells, inhibiting the activation of pro-inflammatory A1 cells, and reducing the damage of neurons caused by inflammation.