Forman M S, Lee V M, Trojanowski J Q
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3400 Spruce Street, Maloney Building, 3rd Floor, Philadelphia, PA 19104, USA.
J Chem Neuroanat. 2000 Dec;20(3-4):225-44. doi: 10.1016/s0891-0618(00)00100-9.
Abundant neurofibrillary lesions consisting of the microtubule associated protein tau and amyloid beta peptide deposits are the defining lesions of Alzheimer's disease. Prominent filamentous tau pathology and brain degeneration in the absence of extracellular amyloid deposition characterize a number of other neurodegenerative disorders (i.e. progressive supranuclear palsy, corticobasal degeneration, Pick's disease) collectively referred to as tauopathies. The discovery of multiple tau gene mutations that are pathogenic for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 in many kindreds, as well as the demonstration that tau polymorphisms are genetic risk factors for sporadic tauopathies, directly implicate tau abnormalities in the onset/progression of neurodegenerative disease. Different tau gene mutations may be pathogenic by impairing the functions of tau or by perturbing the splicing of the tau gene, thereby resulting in biochemically and structurally distinct tau aggregates. However, since specific polymorphisms and mutations in the tau gene lead to diverse phenotypes, it is plausible that additional genetic or epigenetic factors influence the clinical and pathological manifestations of both familial and sporadic tauopathies. Thus, efforts to develop animal models of tau-mediated neurodegeneration should provide further insights into the onset and progression of tauopathies as well as Alzheimer's disease, and they could accelerate research to discover more effective therapies for these disorders.
由微管相关蛋白tau和淀粉样β肽沉积组成的大量神经原纤维病变是阿尔茨海默病的典型病变。在没有细胞外淀粉样蛋白沉积的情况下，显著的丝状tau病理和脑退化是许多其他神经退行性疾病（即进行性核上性麻痹、皮质基底节变性、皮克病）的特征，这些疾病统称为tau蛋白病。在许多家族中发现了多个与17号染色体连锁的遗传性额颞叶痴呆和帕金森病致病的tau基因突变，以及tau基因多态性是散发性tau蛋白病的遗传风险因素，这直接表明tau异常与神经退行性疾病的发病/进展有关。不同的tau基因突变可能通过损害tau的功能或干扰tau基因的剪接而致病，从而导致生化和结构上不同的tau聚集体。然而，由于tau基因中的特定多态性和突变会导致不同的表型，因此很可能还有其他遗传或表观遗传因素影响家族性和散发性tau蛋白病的临床和病理表现。因此，开发tau介导的神经退行性变动物模型的努力应能为tau蛋白病以及阿尔茨海默病的发病和进展提供进一步的见解，并可加速发现针对这些疾病更有效疗法的研究。
