Fundamental study on the molecular mechanism for neuropathological changes of dementia

神经原纤维缠结是阿尔茨海默病中除淀粉样斑块外的主要脑病理改变，在各种痴呆症（称为tau病）中很常见，包括tau蛋白相同或相似的变化。TAU基因能够独立引起FTDP-17等部分痴呆，说明TAU基因编码了主要的致病基因。虽然发现了FTDP- 17的许多变异家族系，但大多数疾病是由外显子10剪接异常引起的。我们从人类基因组中提取了包含外显子10的基因组片段，广泛表征并倡导外显子O剪接的新机制。与Hutton和Schellenberg小组提出的两个模型不同，我们的新模型是基于双茎环结构提出的。在我们的模型中，我们认为位于内含子10下游的第二茎环以负调控的方式与传统的第一茎环合作控制外显子10剪接。此外，为了观察基于该模型的剪接控制不仅在培养细胞中，而且在脑组织中，我们制作了转基因小鼠。它证明了在发育过程中同工异构体变化的所有决定性信息都存在于当前的DNA结构中。基于这个新模型，我们认为tau蛋白多变性（包括阿尔茨海默病的一个阶段）的根本原因不在于tau蛋白本身，而在于影响外显子10表达的剪接机制异常。

Neurofibrillary tangles are the main brain pathological changes beside amyloid plaques in Alzheimer's disease and common in various dementia diseases referred to as tauopachy that include the same or similar changes of tau proteins. TAU gene is independently capable to cause some dementia such as FTDP-17, indicating that TAU gene encodes the major and causative. Although much variation family lines of FTDP- 17 are discovered, the majority of the disease was caused by the abnormalities in splicing of exon 10. We took out the genome fragment including exon 10 in interest from humans and extensively characterized and advocated the new mechanism about exon O splicing.Differently from two models proposed by Hutton and Schellenberg groups, our new model was proposed based on the double stem loop structure. In our model, it was suggested that the 2nd stem loop further in a down stream of intron 10 controlled exon 10 splicing cooperatively with the conventional first stem loop in a negatively regulation manner. Moreover, in order to see the splicing control based on this model in not only culture cells but also brain tissue, we made the transgenic mice. It proved that all the decisive information for an isoform change during development in the present DNA construct. Based on this new model, we think that the essential cause of tauopachy including a phase of Alzheimer's disease is not in tau protein itself, but in the abnormalities of a splicing mechanism that influences an expression of exon 10.