[Jiaotaiwan improves brain glucose metabolism in a mouse model of Alzheimer's disease by activating the PI3K/AKT signaling pathway]

Abstract

Objective: To investigate the effect of Jiaotaiwan on brain insulin-PI3K/AKT pathway in a mouse model of Alzheimer's disease (AD).

Methods: Fifty 3-month-old male APP/PS1 double transgenic mice were randomized into AD model group, low-, medium- and high-dose Jiaotaiwan treatment groups, and donepezil treatment group. Cognitive functions of the mice were assessed using water maze and open field tests, and neuronal pathologies were observed with HE staining and Nissl staining; immunohistochemistry was used to detect amyloid Aβ deposition in the brain. Fasting serum insulin levels of the mice were measured, and the expressions of Aβ₄₂, insulin-PI3K/AKT pathway components and downstream glucose transporters in the brain tissue were detected with RT-qPCR and Western blotting.

Results: The AD mouse models exhibited obvious impairment of learning and memory abilities, significantly reduced hippocampal neurons, and obvious Aβ amyloid plaques in the brain tissue with increased Aβ₄₂ protein expression (P < 0.05) and insulin resistance index, decreased hippocampal PI3K expressions, lowered expressions of AKT and InR, reduced expressions of GLUT1, GLUT3, and GLUT4, and increased expression of GSK3β in both the hippocampus and cortex. Treatment with Jiaotaiwan and donepezil both effectively improved memory ability of the mouse models, increased the number of hippocampal neurons, reduced Aβ amyloid plaques and increased the expressions of PI3K, AKT, InR, GLUT1, GLUT3 and GLUT4 in the hippocampus and cortex.

Conclusion: Jiaotaiwan improves learning and memory abilities of APP/PS1 double transgenic mice and delay the development of AD by activating the PI3K/AKT pathway and regulating the expression levels of its downstream GLUTs in the brain.

Keywords: Alzheimer's disease; Jiaotaiwan; glucose metabolism; glucose transporter proteins; insulin PI3K/AKT pathway.

图1

各组小鼠Morris水迷宫实验以及旷场实验结果比较 Fig.1 Results of Morris water maze test and open field test. A: Comparison of escape latency of the mice among the groups (Mean±SD, n=8). B: Swimming trajectories during escape latency in each group. C: Open field behavior trajectories of the mice in each group. ***P<0.001 vs Control group; ^## P<0.01, ^### P<0.001 vs model group.

图2

交泰丸对各组小鼠海马神经元形态的影响 Fig.2 Effect of Jiaotaiwan on hippocampal neuron morphology in each group. A: Representative HE staining results of the hippocampus in each group. B: Nissl staining of the hippocampus in each group (scale bar=100 μm).

图3

交泰丸对各组小鼠海马、皮质Aβ斑块聚集和Aβ₄₂含量的影响 Fig.3 Impact of Jiaotaiwan on aggregation of Aβ plaques and Aβ₄₂ level in the hippocampus and cortex of the mice (Mean±SD, n=4). A: Immunohistochemistry showing Aβ plaques in the hippocampus and cortex (scale bar=100 μm. B: Quantification of Aβ₄₂ protein expressions in the hippocampus and cortex using Western blotting. *P<0.05,***P<0.001 vs Control group; ^## P<0.01,^### P<0.001 vs Model group.

图4

交泰丸对各组小鼠海马、皮质胰岛素PI3K/AKT通路相关指标的影响 Fig.4 Effects of Jiaotaiwan on insulin-PI3K/AKT pathway in the hippocampus and cortex of the mice in each group. A: Western blots of the proteins in the insulin-PI3K/AKT pathway in the hippocampus and cortex in each group. B: Comparison of PI3K, AKT, GSK3β, and InR protein and mRNA expressions in the hippocampus and cortex among the groups (Mean±SD).*P<0.05,**P<0.01,***P<0.001 vs Control group; ^# P<0.05,^## P<0.01,^### P<0.001 vs Model group.

图5

交泰丸对各组小鼠海马、皮质葡萄糖转运相关指标的影响 Fig.5 Effects of Jiaotaiwan on glucose transport in the hippocampus and cortex of the mice in each group. A: Western blots of the proteins involved in glucose transport in the hippocampus and cortex in each group. B: Expression levels of GLUT1, GLUT3, and GLUT4 proteins and mRNAs in the hippocampus and cortex in each group (Mean±SD).*P<0.05, **P<0.01, ***P<0.001 vs Control group; ^# P<0.05, ^## P<0.01, ^### P<0.001 vs Model group.