Vickers J C, Morrison J H, Friedrich V L, Elder G A, Perl D P, Katz R N, Lazzarini R A
Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029-6574.
J Neurosci. 1994 Sep;14(9):5603-12. doi: 10.1523/JNEUROSCI.14-09-05603.1994.
Alterations in neurofilaments are a common occurrence in neurons of the human nervous system during aging and diseases associated with aging. Such pathologic changes may be attributed to species-specific properties of human neurofilaments as well as cell-type-specific regulation of this element of the cytoskeleton. The development of transgenic animals containing human neurofilament subunits offers an opportunity to study the effects of aging and other experimental conditions on the human-specific form of these proteins in a rodent model. The present study shows that mice from the transgenic line NF(M)27, which express the human midsized neurofilament subunit at low levels (2-25% of the endogenous NF-M), develop neurofilamentous accumulations in specific subgroups of neurons that are age dependent, affecting 78% of transgenic mice over 12 months of age. Similar accumulations do not occur in age-matched, wild-type littermates or in 3-month-old transgenic mice. In 12-month-old transgenic mice, somatic neurofilament accumulations resembling neurofibrillary tangles were present predominantly in layers III and V of the neocortex, as well as in select subpopulations of subcortical neurons. Intraperikaryal, spherical neurofilamentous accumulations were particularly abundant in cell bodies in layer II of the neocortex, and neurofilament-containing distentions of Purkinje cell proximal axons occurred in the cerebellum. These pathological accumulations contained mouse as well as human NF subunits, but could be distinguished by their content of phosphorylation-dependent NF epitopes. These cytoskeletal alterations closely resemble the cell-type-specific alterations in neurofilaments that occur during normal human aging and in diseases associated with aging, indicating that these transgenic animals may serve as models of some aspects of the pathologic features of human neurodegenerative diseases.
在衰老过程以及与衰老相关的疾病中，神经丝的改变在人类神经系统的神经元中普遍存在。这种病理变化可能归因于人类神经丝的物种特异性特性以及细胞类型对这种细胞骨架成分的特异性调节。含有人类神经丝亚基的转基因动物的培育为在啮齿动物模型中研究衰老和其他实验条件对这些蛋白质人类特异性形式的影响提供了机会。本研究表明，来自转基因系NF(M)27的小鼠，其低水平表达人类中型神经丝亚基（内源性NF-M的2%-25%），在特定的神经元亚群中出现与年龄相关的神经丝堆积，12个月以上的转基因小鼠中有78%受影响。在年龄匹配的野生型同窝小鼠或3个月大的转基因小鼠中未出现类似的堆积。在12个月大的转基因小鼠中，类似神经原纤维缠结的体细胞神经丝堆积主要存在于新皮层的III层和V层，以及皮质下神经元的特定亚群中。核周球形神经丝堆积在新皮层II层的细胞体中尤为丰富，小脑浦肯野细胞近端轴突出现含神经丝的扩张。这些病理堆积物包含小鼠和人类的NF亚基，但可通过其磷酸化依赖性NF表位的含量加以区分。这些细胞骨架改变与正常人类衰老过程以及与衰老相关疾病中神经丝发生的细胞类型特异性改变极为相似，表明这些转基因动物可作为人类神经退行性疾病某些病理特征方面的模型。
