Pathogenesis of Tauopathies

聚集性微管相关蛋白tau （tau）是一组具有异质临床和神经病理表现的神经退行性疾病的常见病变，统称为tau病。与临床和病理多样性一致，病理性tau聚集物具有诱导正常tau以菌株依赖的方式聚集的生物学效力，这提示了疾病特异性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传播的机制，并寻找抑制传播过程的治疗靶点。核心假设是tau菌株的印迹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菌株差异传播的机制将通过抑制tau发病机制中的关键传播步骤，促进治疗靶点的发展，以选择性和有效地治疗不同形式的tau病。我们的具体目的是验证以下假设：（目标1）β淀粉样蛋白斑块病理与不同形式的tau病理相互作用并调节tau的传递；（目的2）病理构象的转换是tau菌株依赖致病性的分子基础；（目的3）调节tau蛋白传递的新基因可以作为tau病的治疗策略。这一贡献具有重要意义，因为该研究将阐明牛头病多样性的分子基础，并提供治疗疾病的具体策略。这项研究具有创新性，因为我们将使用新的tau病模型来研究tau传播的时空机制，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.