IMDEA-Food, CEI UAM+CSIC, Madrid, Spain.
Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla-La Mancha, Toledo, Spain.
Biofactors. 2017 Jul 8;43(4):540-548. doi: 10.1002/biof.1356. Epub 2017 Mar 20.
Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50-100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD. We hypothesized that hydroxytyrosol (HT, the preeminent polyphenol of olives and olive oil) could exert beneficial effects on IR associated with AD and investigated it mechanisms of action in an astrocytic model of AD. The astrocytic cell line C6 was exposed to Aβ(25-35) and co-incubated with HT for different periods. After treatment with Aβ(25-35), astrocytes' viability was significantly decreased as compared with controls; however, both pre- and post-treatment with HT prevented this effect. Mechanistically, we found that the preventive role of HT on Aβ(25-35)- induced cytotoxicity in astrocytes is moderated by an increased HT-induced activation of Akt, which is mediated by the insulin signaling pathway. In addition, we report that HT prevented the pronounced activation of mTOR, thereby restoring proper insulin signaling. In conclusion, we demonstrate that HT protects Aβ(25-35)-treated astrocytes by improving insulin sensitivity and restoring proper insulin-signaling. These data provide some mechanistic insight on the observed inverse association between olive oil consumption and prevalence of cognitive impairment. © 2017 BioFactors, 43(4):540-548, 2017.
最近的流行病学证据表明，糖尿病是 AD 发病和发展的一个危险因素。事实上，对纵向流行病学研究的荟萃分析表明，糖尿病使 AD 的风险增加了 50-100%，胰岛素抵抗（IR）是糖尿病与 AD 之间的主要联系。星形胶质细胞是大脑中首要的大胶质细胞，负责将葡萄糖转化为乳酸，并将其转移到神经元中作为燃料，但 Aβ（1-42）会损害胰岛素信号和糖原储存。最近的前瞻性研究表明，地中海饮食与 AD 的发病率较低有关。我们假设羟基酪醇（HT，橄榄和橄榄油的主要多酚）可能对与 AD 相关的 IR 产生有益的影响，并在 AD 的星形胶质细胞模型中研究其作用机制。星形胶质细胞系 C6 暴露于 Aβ（25-35）中，并与 HT 共同孵育不同时间。用 Aβ（25-35）处理后，与对照相比，星形胶质细胞的活力明显降低；然而，HT 的预先和后处理均可预防这种作用。从机制上讲，我们发现 HT 通过增加 Akt 的激活来调节 HT 对 Aβ（25-35）诱导的星形胶质细胞细胞毒性的预防作用，而 Akt 的激活是由胰岛素信号通路介导的。此外，我们报告 HT 阻止了 mTOR 的显著激活，从而恢复了适当的胰岛素信号。总之，我们证明 HT 通过改善胰岛素敏感性和恢复适当的胰岛素信号来保护 Aβ（25-35）处理的星形胶质细胞。这些数据为观察到橄榄油消耗与认知障碍发生率之间的相反关联提供了一些机制上的见解。
