Department of Biological Sciences, Center for Cellular Neuroscience and Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA, USA.
J Alzheimers Dis. 2010;19(2):647-64. doi: 10.3233/JAD-2010-1273.
The mechanisms by which tau-containing lesions are propagated between adjacent and synaptically interconnected parts of the brain are a potentially important but poorly understood component of human tauopathies such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Since the utility of currently available transgenic models for studying intercellular aspects of tauopathy is limited by their broad patterns of tau expression in the central nervous system, we used an in situ tauopathy model that replicates tau-induced cytodegeneration in identified neurons on a tau-negative background to determine whether tau secretion or interneuronal transfer might play a role in lesion propagation. We found that the N-terminal half of tau is required for tau secretion and is efficiently exported to the extracellular space and adjacent neurons at relatively low levels of overexpression. By contrast, full-length tau is secreted by a separate mechanism that is correlated with phosphorylation of tau at tyrosine 18 and dendritic degeneration, is exacerbated by tauopathy mutations, and blocked by mutations that inhibit tau:tau interactions. Anterograde transneuronal tau movement occurred with the expression of tau containing the P301L tauopathy mutant, but not with wild type tau isoforms. Our results are consistent with recent studies suggesting a role for molecular "templating" in the propagation of neurofibrillary lesions and provide a novel conceptual and experimental basis for studying the mechanisms of interneuronal propagation and toxicity in human neurodegenerative disease.
在阿尔茨海默病、皮克病和皮质基底节变性等人类 tau 病中，tau 包含的病变在相邻的、突触相互连接的大脑部位之间传播的机制是一个潜在的重要但了解甚少的组成部分。由于目前可用于研究 tau 病细胞间方面的转基因模型的实用性受到其在中枢神经系统中广泛表达 tau 的限制，我们使用了一种原位 tau 病模型，该模型在 tau 阴性背景下复制了 tau 诱导的特定神经元中的细胞变性，以确定 tau 分泌或神经元间转移是否可能在病变传播中发挥作用。我们发现，tau 的 N 端一半对于 tau 的分泌是必需的，并且可以在相对低的过表达水平下有效地被运送到细胞外空间和相邻的神经元中。相比之下，全长 tau 通过一种独立的机制分泌，该机制与 tau 在酪氨酸 18 处的磷酸化和树突变性相关，tau 病突变会加剧这种机制，而抑制 tau:tau 相互作用的突变则会阻断这种机制。tau 包含 P301L tau 病突变的表达会导致顺行性跨神经元 tau 运动，但野生型 tau 同工型则不会。我们的结果与最近的研究一致，这些研究表明分子“模板”在神经纤维状病变的传播中起作用，并为研究人类神经退行性疾病中神经元间传播和毒性的机制提供了新的概念和实验基础。
