Lester-Coll Nataniel, Rivera Enrique J, Soscia Stephanie J, Doiron Kathryn, Wands Jack R, de la Monte Suzanne M
Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA.
J Alzheimers Dis. 2006 Mar;9(1):13-33. doi: 10.3233/jad-2006-9102.
The cascade of Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress, mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral Streptozotocin (ic-STZ), that chemical depletion of insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated blood glucose levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, active glycogen synthase kinase 3beta, phospho-tau, ubiquitin, and amyloid-beta. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes.
阿尔茨海默病（AD）神经退行性变的级联反应与持续的氧化应激、线粒体功能障碍、能量代谢受损以及促死亡信号通路的激活有关。最近，对人类尸检脑组织的研究将AD的许多特征性分子和病理特征与胰岛素和胰岛素样生长因子（IGF）基因及其相应受体的表达降低联系起来。我们现在使用脑室内链脲佐菌素（ic-STZ）的体内模型证明，胰岛素和IGF信号机制的化学耗竭与氧化损伤相结合足以导致AD型神经退行性变。注射ic-STZ的大鼠血糖水平没有升高，胰腺结构和胰岛素免疫反应性与对照组相似，但其大脑体积减小，并表现出与细胞丢失、胶质增生以及p53、活性糖原合酶激酶3β、磷酸化tau、泛素和淀粉样β蛋白免疫反应性增加相关的神经退行性变。实时定量RT-PCR研究表明，ic-STZ处理的大脑中与神经元、少突胶质细胞和胆碱乙酰转移酶相对应的基因表达显著降低，而编码胶质纤维酸性蛋白、小胶质细胞特异性蛋白、乙酰胆碱酯酶、tau和淀粉样前体蛋白的基因表达增加。这些异常与编码胰岛素、IGF-II、胰岛素受体、IGF-I受体和胰岛素受体底物-1的基因表达降低以及胰岛素和IGF-II受体的配体结合减少有关。这些结果表明，AD型神经退行性变的许多特征可以通过选择性损害胰岛素/IGF功能并增加氧化应激来实验性地产生，并支持我们的假设，即AD代表一种与胰岛素和IGF信号机制中的脑特异性扰动相关的神经内分泌疾病，即3型糖尿病。
