Pathogenesis of Tauopathies

聚集的微管相关蛋白tau（Aggregated microtubule-associated protein tau，tau）是一组临床和病理表现异质性的神经退行性疾病的常见病变，统称为tau蛋白病。与临床和病理学多样性一致，病理性tau聚集体在生物学上有效地以菌株依赖性方式诱导正常tau聚集，表明疾病特异性tau发病机制的潜在机制。该研究的长期目标是阐明菌株依赖性tau蛋白传递的机制，并寻找抑制传递过程的治疗靶点。中心假设是tau蛋白的印记特性通过传递活动损害神经元生物学。我们的基本原理是，了解tau菌株差异传递的机制将有助于开发治疗靶点，通过抑制tau发病机制中的关键传递步骤来选择性和有效地治疗不同形式的tau病变。我们的具体目标是验证以下假设：（目的1）淀粉样β蛋白斑块病理学与不同形式的tau病理学相互作用并调节tau传递;（目的2）病理构象的转换是tau菌株依赖性致病性的分子基础;（目的3）调节tau传递的新基因可以作为tau病变的治疗策略。这一贡献是重要的，因为该研究将阐明tau蛋白病多样性的分子基础，并提供治疗疾病的具体策略。这项研究是创新的，因为我们将使用新的tau蛋白病模型来时空研究tau蛋白传递的机制，并寻找与疾病高度相关的潜在治疗靶点。

Aggregated microtubule-associated protein tau (tau) is the common lesion of a group of neurodegenerative diseases with heterogeneous clinical and neuropathological manifestations, collectively referred to as tauopathies. In line with the clinical and pathological diversity, pathological tau aggregates are biologically potent to induce normal tau into aggregations in a strain-dependent manner, suggesting an underlying mechanism of disease-specific tau pathogenesis. The long-term goal of the study is to elucidate the mechanism(s) of the strain-dependent tau transmission and search for therapeutic targets to inhibit the transmission procedure. The central hypothesis is that the imprinted properties of tau strain impair neuron biology via transmission activities. Our rationale is that understanding the mechanism by which tau strains differentially transmit will facilitate the development of therapeutic targets to selectively and efficiently treat different forms of tauopathy by inhibiting the critical transmission steps in tau pathogenesis. Our specific aims are to test the following hypotheses: (Aim 1) amyloid β plaques pathology interact with different forms of tau pathology and modulate of tau transmission; (Aim 2) the conversion of pathological conformations is the molecular basis of tau strain-dependent pathogenicity; (Aim 3) novel genes modulating tau transmission can be targeted as therapeutic strategies for tauopathy. This contribution is significant since the study will elucidate the molecular basis of the diversity of tauopathy and provide specific strategies to treat the diseases. The proposed research is innovative because we will use novel models of tauopathy to spatiotemporally investigate the mechanism of tau transmission and search for potential therapeutic targets with a high degree of disease relevance.