Intranasal 15d-PGJ2 ameliorates brain glucose hypometabolism via PPARγ-dependent activation of PGC-1α/GLUT4 signalling in APP/PS1 transgenic mice
Intranasal 15d-PGJ2 ameliorates brain glucose hypometabolism via PPARγ-dependent activation of PGC-1α/GLUT4 signalling in APP/PS1 transgenic mice
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鼻内 15d-PGJ2 通过 PPARγ 依赖性激活 APP/PS1 转基因小鼠中的 PGC-1α/GLUT4 信号改善脑葡萄糖代谢低下
DOI：
10.1016/j.neuropharm.2021.108685
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发表时间：
2021-07-05
影响因子：
4.7
通讯作者：
Huang, Guodong
中科院分区：
文献类型：
--
作者：
Li, Zongyang;Zhang, Yuan;Huang, Guodong
针对2型糖尿病和阿尔茨海默病（AD）的共同分子机制，包括糖代谢失调、胰岛素抵抗和神经炎症，可能是AD的有效治疗策略。先前的研究表明，15-脱氧-Δ 12，14-前列腺素J2（15 d-PGJ 2）是一种内源性PPAR γ激动剂，具有抗炎、胰岛素增敏和抗糖尿病作用。然而，15 d-PGJ 2是否对AD具有有益作用仍有待阐明。在本研究中，我们发现，鼻内给药15 d-PGJ 2（300 ng/30 μ L/天）3个月显著抑制A β斑块，抑制神经炎症，并减弱APP/PS1转基因小鼠的认知缺陷。有趣的是，15 d-PGJ 2处理可以增加脑葡萄糖摄取，如通过F-18-FDG microPET成像以及APP/PS1小鼠海马中GLUT 4和NeuN的共定位所检测到的。此外，15 d-PGJ 2显著增加APP/PS1小鼠海马中的PPAR γ和PGC-1 α的表达，上调GLUT 4，并降低IRS-1（Ser 616）的磷酸化。重要的是，共同施用的PPAR γ拮抗剂GW 9662废除这些保护作用的15 d-PGJ 2。总的来说，鼻内15 d-PGJ 2通过激活PPAR γ依赖性PGC-1 α/GLUT 4信号传导而赋予针对AD的保护作用。PPAR γ激动剂15 d-PGJ 2可能是一种潜在的治疗AD的药物。
Targeting the common molecular mechanism of type 2 diabetes mellitus and Alzheimer's disease (AD), including dysregulation of glucose metabolism, insulin resistance, and neuroinflammation, might be an efficient treatment strategy for AD. Previous studies have shown that 15-deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2), an endogenous PPAR gamma agonist, has anti-inflammatory, insulin sensitizing and anti-diabetic effects. However, whether 15d-PGJ2 has beneficial effects on AD remains to be elucidated. In the present study, we found that intranasal administration of 15d-PGJ2 (300 ng/30 mu L/day) for 3 months significantly inhibited A beta plaques, suppressed neuroinflammation, and attenuated cognitive deficits in APP/PS1 transgenic mice. Interestingly, 15d-PGJ2 treatment could increase brain glucose uptake, as detected by F-18-FDG microPET imaging, and co-localization of GLUT4 and NeuN in the hippocampus of APP/PS1 mice. Furthermore, 15d-PGJ2 markedly increased the expression of PPAR gamma and PGC-1 alpha, upregulated GLUT4, and decreased the phosphorylation of IRS-1 (Ser616) in the hippocampus of APP/PS1 mice. Importantly, co-administration of a PPAR gamma antagonist GW9662 abrogated these protective effects of 15d-PGJ2. Collectively, intranasal 15d-PGJ2 conferred protective effects against AD by activating PPAR gamma-dependent PGC-1 alpha/GLUT4 signalling. The PPAR gamma agonist 15d-PGJ2 might be a potential therapeutic drug for AD.