Investigating the Propagation and Pattern of Spread of Unique Tau Strains

描述(由申请人提供)：tau病是一组不同的神经退行性疾病，其特征是聚集的tau蛋白积聚。最近的证据表明，错误折叠的tau跨细胞传播导致了在这些疾病中观察到的典型的病理进展。不同的tau聚集体构象或菌株可能导致tau病中观察到的表型多样性和独特的病理扩散模式，就像在传染性海绵状脑病(TSE)中观察到的那样。我们最近分离出了不同的tau菌株，它们在细胞培养中稳定繁殖独特的聚集体构象。将这些独特的tau细胞株注射到小鼠tau病模型中，可以产生不同的tau组织病理学模式，这表明构象确实可能影响tau病理模式。这项提议将利用这种菌株接种模型来测试不同的tau构象是否能够在体内稳定繁殖。这将直接测试tau是否可以在动物系统中扮演真正的Prion的角色。这项提议随后将测试构象对tau病理通过大脑传播模式的影响。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，并将提供关键的洞察力，以了解tau病背后的病理生理学。最后，这项建议将测试抑制硫酸乙酰肝素蛋白多糖(HSPG)的合成，这是聚集的tau内吞所必需的，是否可以防止tau病理的传播。这将测试HSPG介导的摄取作为一种新的治疗靶点，并将提供对tau病理进展的机械性洞察。

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.