Nanobodies selective for oligomeric Tau species isolated from AD brain

描述(申请人提供)：蛋白质错误折叠和聚集是许多神经退行性疾病背后的共同线索，包括阿尔茨海默病(AD)、路易体痴呆(LBD)和帕金森病(PD)等。虽然每种疾病都主要与一种特定蛋白质的聚集有关；β-淀粉样蛋白(ABETA)与AD、tau与AD和其他tau病、α-突触核蛋白(a-syn)与PD和LBD有关，但不止一种蛋白质可能在脑组织中错误折叠和聚集，从而使诊断和治疗策略复杂化。虽然所有这些蛋白质都可以形成纤维状聚集体，但它们也可以形成各种 不同的较小的可溶团聚体结构也不同。研究表明，小分子可溶性蛋白质 聚集体是各种疾病中相关的有毒物种，而不是作为诊断标志的纤维聚集体。这些蛋白质中的每一种在体外和体内都可以存在多种不同的中间寡聚形式，不同的聚集形式可以对细胞产生不同的毒性作用，并可能优先针对不同类型的细胞。由于一种蛋白质如abeta的错误折叠和聚集引起的细胞应激很可能导致其他蛋白质如tau和a-syn的错误折叠和聚集，因此在不同的疾病中可能会出现多个错误折叠的蛋白质。因此，确定哪些聚集蛋白种类与每种疾病的不同阶段相关，将极大地促进制定更好的诊断和治疗策略。我们已经产生了几种特性良好的试剂，它们专门识别不同的abeta和a-syn聚集物种，并证明了这些试剂识别发生在患病大脑组织中的聚集物种，但不识别健康大脑，并且这些试剂也可以具有疾病特异性。在这里，我们将开发和测试类似的试剂来检测AD脑组织中存在的特定形式的tau。

DESCRIPTION (provided by applicant): Protein misfolding and aggregation is a common thread behind many neurodegenerative diseases including Alzheimer's disease (AD), Lewy Body Dementia (LBD), and Parkinson's disease (PD) among others. While each disease has been primarily associated with aggregation of a specific protein; beta-amyloid (abeta) with AD, tau with AD and other tauopathies, alpha- synuclein (a-syn) with PD and LBD, more than one protein is likely to misfold and aggregate in brain tissue complicating diagnosis and treatment strategies. While all these proteins can form fibrillar aggregates, they can also form a variety of different smaller soluble aggregate structures as well. Studies indicate that small soluble protein aggregate forms are the relevant toxic species in the various diseases rather than the fibrillar aggregates that serve as diagnostic hallmarks. A variety of different intermediate oligomeric forms of each of these proteins can exist in vitro and in vivo, and different aggregate forms can have different toxic effects on cells, and may preferentially target different types of cells. Sinc cellular stress induced by misfolding and aggregation of one protein such as abeta may well lead to misfolding and aggregation of other proteins such as tau and a-syn, the presence of multiple misfolded proteins in different diseases should be expected. Therefore characterizing which aggregated protein species are correlated with different stages of each disease would greatly facilitate development of better diagnostic and treatment strategies. We have generated several well characterized reagents that specifically recognize different aggregated species of abeta and a-syn, and have demonstrated that the reagents recognize aggregated species occurring in tissue from diseased brains, but not healthy brains, and that the reagents can have disease specificity as well. Here we will develop and test similar reagents for detecting specific forms of tau that are present in AD brain tissue.