Brion J P
Laboratory of Pathology and Electron Microscopy, Université Libre de Bruxelles, Brussels, Belgium.
Eur Neurol. 1998 Oct;40(3):130-40. doi: 10.1159/000007969.
The neuropathological diagnosis of Alzheimer's disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrillary tangles formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurons, even before formation of neurofibrillary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenon. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrillary tangles and phosphorylated tau species is associated with disturbances of the microtubule network and, as a consequence of the latter, of axoplasmic flows. The mechanistic relationship between the formation of neurofibrillary tangles and senile plaques is still little understood and in vivo formation of neurofibrillary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully reproduce faithfully all the major cellular lesions of the disease.
阿尔茨海默病的神经病理学诊断依赖于神经原纤维缠结和老年斑的存在。神经原纤维缠结的数量与痴呆程度紧密相关，这表明神经原纤维缠结的形成与神经元功能障碍更直接相关。在疾病过程中，受神经原纤维缠结形成影响的区域模式相对固定。神经原纤维缠结由微管相关蛋白tau的高度磷酸化形式组成。磷酸化的tau蛋白在神经元中早期积累，甚至在神经原纤维缠结形成之前，这表明作用于tau的蛋白激酶和磷酸酶活性之间的失衡是一种早期现象。后者可能与通过转导级联的信号变化有关，因为许多产生磷酸化tau物种的蛋白激酶参与信号通路。神经原纤维缠结和磷酸化tau物种的积累与微管网络的紊乱有关，并且由于后者，与轴浆流动有关。神经原纤维缠结和老年斑形成之间的机制关系仍知之甚少，并且尚未在实验模型中实现神经原纤维缠结的体内形成。未来的动物模型，例如表达联合关键人类蛋白的转基因动物，有望忠实地重现该疾病的所有主要细胞损伤。
