Frölich L, Blum-Degen D, Bernstein H G, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Türk A, Hoyer S, Zöchling R, Boissl K W, Jellinger K, Riederer P
Department of Psychiatry I, University of Frankfurt/Main, Federal Republic of Germany.
J Neural Transm (Vienna). 1998;105(4-5):423-38. doi: 10.1007/s007020050068.
The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.
寻找神经退行性疾病的病因是脑研究的一个主要课题。在散发性阿尔茨海默病（SDAT）中，细胞代谢多个方面的后天性紊乱在病理上显得很重要。其中，在疾病早期大脑葡萄糖利用率降低，且对葡萄糖代谢重要的调节酶减少。在大脑中，胰岛素、胰岛素样生长因子及其受体调节葡萄糖代谢并促进神经元生长。为了检测SDAT患者脑胰岛素神经调节系统功能活性的变化，我们测定了衰老和患阿尔茨海默病期间死后大脑皮质几个区域中胰岛素和C肽的浓度以及胰岛素受体结合和IGF-I受体结合情况。此外，我们用抗胰岛素抗体对SDAT患者和对照者的新皮质脑区进行了免疫组织化学染色。我们首次表明，大脑中胰岛素和C肽浓度相互关联且随衰老而降低，脑胰岛素受体密度也是如此。在对照组的锥体细胞中可通过组织化学方法证明有弱胰岛素免疫反应性，而在SDAT患者中发现有较强的胰岛素免疫反应性。在生化水平上，与中年对照组相比，胰岛素和C肽水平降低，但与年龄匹配的对照组相比则无变化。与中年对照组相比，SDAT患者的脑胰岛素受体密度降低，但与年龄匹配的对照组相比则升高。在衰老和SDAT患者中IGF-I受体密度无变化。酪氨酸激酶活性是两种受体系统共有的信号转导机制，与中年和年龄匹配的对照组相比，SDAT患者中的该活性降低。这些数据与胰岛素在人类大脑中的神经营养作用以及SDAT大脑中胰岛素信号转导紊乱一致，支持胰岛素依赖性功能可能在散发性SDAT发病机制中具有相关性这一假说。
