Sun Ping, Ortega Gabriela, Tan Yan, Hua Qian, Riederer Peter F, Deckert Jürgen, Schmitt-Böhrer Angelika G
Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Science & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
Front Aging Neurosci. 2018 May 18;10:145. doi: 10.3389/fnagi.2018.00145. eCollection 2018.
Rats intracerebroventricularily (icv) treated with streptozotocin (STZ), shown to generate an insulin resistant brain state, were used as an animal model for the sporadic form of Alzheimer's disease (sAD). Previously, we showed in an study that 3 months after STZ icv treatment hippocampal adult neurogenesis (AN) is impaired. In the present study, we examined the effects of STZ on isolated adult hippocampal neural stem cells (NSCs) using an approach. We revealed that 2.5 mM STZ inhibits the proliferation of NSCs as indicated by reduced number and size of neurospheres as well as by less BrdU-immunoreactive NSCs. Double immunofluorescence stainings of NSCs already being triggered to start with their differentiation showed that STZ primarily impairs the generation of new neurons, but not of astrocytes. For revealing mechanisms possibly involved in mediating STZ effects we analyzed expression levels of insulin/glucose system-related molecules such as the glucose transporter (GLUT) 1 and 3, the insulin receptor (IR) and the insulin-like growth factor (IGF) 1 receptor. Applying quantitative Real time-PCR (qRT-PCR) and immunofluorescence stainings we showed that STZ exerts its strongest effects on GLUT3 expression, as GLUT3 mRNA levels were found to be reduced in NSCs, and less GLUT3-immunoreactive NSCs as well as differentiating cells were detected after STZ treatment. These findings suggest that cultured NSCs are a good model for developing new strategies to treat nerve cell loss in AD and other degenerative disorders.
用链脲佐菌素（STZ）进行脑室内（icv）注射处理的大鼠，已证明会产生胰岛素抵抗性脑状态，被用作散发性阿尔茨海默病（sAD）的动物模型。此前，我们在一项研究中表明，STZ脑室内注射处理3个月后，海马体成年神经发生（AN）受损。在本研究中，我们采用一种体外方法研究了STZ对分离的成年海马神经干细胞（NSCs）的影响。我们发现，2.5 mM的STZ抑制了神经干细胞的增殖，这表现为神经球数量和大小减少，以及BrdU免疫反应性神经干细胞数量减少。对已经开始分化的神经干细胞进行双重免疫荧光染色显示，STZ主要损害新神经元的生成，而不影响星形胶质细胞的生成。为了揭示可能介导STZ作用的机制，我们分析了胰岛素/葡萄糖系统相关分子的表达水平，如葡萄糖转运蛋白（GLUT）1和3、胰岛素受体（IR）以及胰岛素样生长因子（IGF）1受体。应用定量实时PCR（qRT-PCR）和免疫荧光染色，我们发现STZ对GLUT3表达的影响最为显著，因为在神经干细胞中发现GLUT3 mRNA水平降低，并且在STZ处理后检测到较少的GLUT3免疫反应性神经干细胞以及分化细胞。这些发现表明，培养的神经干细胞是开发治疗AD和其他退行性疾病中神经细胞丢失新策略的良好模型。
