Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain.
Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona, Spain.
Mol Neurobiol. 2020 Jan;57(1):551-565. doi: 10.1007/s12035-019-01708-4. Epub 2019 Aug 9.
Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11β-HSD1i. Remarkably, treatment with 11β-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11β-HSD1i for the treatment of age-related cognitive decline and AD.
衰老和肥胖已被证明会增加认知能力下降和阿尔茨海默病（AD）的风险。此外，升高的糖皮质激素（GCs）水平会导致代谢应激，并与神经退行性过程相关。直接的证据表明，通过抑制 11β-羟类固醇脱氢酶 1 型（11β-HSD1）降低 GCs 水平与认知改善有关。在本研究中，我们研究了 11β-HSD1 抑制剂（i）RL-118 在高脂肪饮食（HFD）治疗衰老加速小鼠易感 8 型（SAMP8）中的有益作用。我们发现 RL-118 治疗可改善 HFD 诱导的葡萄糖不耐受，显著降低 11β-HSD1 和糖皮质激素受体（GR）蛋白水平。此外，在 11β-HSD1i 治疗后发现 FGF21 激活的特异性改变，即 RL-118 诱导 SIRT1/PGC1α/AMPKα 通路发生变化。在 HFD 小鼠中，氧化应激（OS）和活性氧（ROS）以及炎症标志物和小胶质细胞激活显著减少。值得注意的是，在两种饮食组中，11β-HSD1i 改变 PERK 通路，仅在 HFD 小鼠组中增加自噬。RL-118 治疗后，发现糖原合酶激酶 3（GSK3β）激活、Tau 过度磷酸化、BACE1 蛋白水平和产物 β-CTF 减少。在两种治疗的小鼠中都发现非淀粉样β分泌酶 ADAM10 蛋白水平和产物 sAPPα 增加，而不论饮食如何。因此，在治疗的小鼠中发现对社会行为和认知表现有有益的影响。因此，我们的结果支持选择性 11β-HSD1i 治疗与年龄相关的认知能力下降和 AD 的治疗策略。
