Investigating the Propagation and Pattern of Spread of Unique Tau Strains

描述（由申请人提供）：Tau蛋白病是一组不同的神经退行性疾病，其特征在于聚集的Tau蛋白的积累。最近的证据表明，错误折叠的tau蛋白的跨细胞扩散导致在这些疾病中观察到的病理学的刻板进展。不同的tau聚集体构象或菌株可能导致在tau蛋白病中观察到的病理学扩散的表型多样性和独特模式，如在传染性海绵状脑病（TSE）中观察到的。我们最近已经分离出不同的tau菌株，其在细胞培养物中稳定地繁殖独特的聚集体构象。将这些独特的细胞tau菌株注射到鼠tau病变模型中产生不同的tau组织病理学模式，表明构象可能确实影响tau病理学模式。该提案将使用该菌株接种模型来测试不同的tau构象是否可以在体内稳定繁殖。这将直接测试tau蛋白是否可以在动物系统中充当真正的朊病毒。然后，该提案将测试构象对tau病理在大脑中传播模式的影响。这将测试不同的tau聚集体构象是否可以导致独特的病理模式，并将提供对tau蛋白病基础的病理生理学的重要见解。最后，该提案将测试抑制硫酸乙酰肝素蛋白聚糖（HSPG）合成（其是聚集的tau的内吞作用所需的）是否可以防止tau病理的这种传播。这将测试HSPG介导的摄取作为新的治疗靶点，并将提供对tau病理学进展的机制见解。

DESCRIPTION (provided by applicant): Tauopathies are a diverse group of neurodegenerative diseases characterized by the accumulation of aggregated tau protein. Recent evidence suggests that transcellular spread of misfolded tau leads to the stereotypical progression of pathology observed in these diseases. Different tau aggregate conformations, or strains, may lead to the phenotypic diversity and unique patterns of spread of pathology observed in tauopathies, as has been observed in transmissible spongiform encephalopathies (TSEs). We have recently isolated distinct tau strains that stably propagate unique aggregate conformations in cell culture. Injection of these unique cellular tau strains into a murine tauopathy model produces different patterns of tau histopathology, suggesting conformation may indeed influence the pattern of tau pathology. This proposal will use this strain inoculation model to test whether different tau conformations can stably propagate in vivo. This will directly test whether tau can act as a true prion in an animal system. This proposal will then test the effect of conformation on the pattern of spread of tau pathology through the brain. This will test whether distinct tau aggregate conformations can lead to unique patterns of pathology, and will provide critical insight into the pathophysiology that underlies tauopathies. Finally, this proposa will test whether inhibition of heparan sulfate proteoglycan (HSPG) synthesis, which is required for endocytosis of aggregated tau, can prevent this spread of tau pathology. This will test HSPG-mediated uptake as a novel therapeutic target, and will provide mechanistic insight into the progression of tau pathology.