Nanobodies selective for oligomeric Tau species isolated from AD brain

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。 包括阿尔茨海默氏病（AD）、路易体痴呆（LBD）和帕金森氏病的疾病 疾病（PD）。虽然每种疾病都主要与聚集有关， 一种特定的蛋白质; β-淀粉样蛋白（abeta）与AD，tau与AD和其他tau蛋白病，α- 突触核蛋白（α-syn）与PD和LBD，一个以上的蛋白质可能错误折叠和聚集在 脑组织并发症的诊断和治疗策略。虽然所有这些蛋白质都可以形成 纤维状聚集体，它们还可以形成各种不同的较小的可溶性聚集体结构 也研究表明，小的可溶性蛋白质聚集体形式是相关的毒性 在各种疾病中，蛋白质的种类，而不是用作诊断的纤维状聚集体， 特征这些蛋白质中的每一种的各种不同的中间寡聚体形式可以 存在于体外和体内，不同的聚集体形式对细胞有不同的毒性作用， 并且可以优先靶向不同类型的细胞。由于错误折叠引起的细胞应激 一种蛋白质如Abeta的聚集很可能导致蛋白质的错误折叠和聚集。 其他蛋白质如tau和a-syn，在不同的细胞中存在多个错误折叠的蛋白质， 疾病是可以预见的。因此，表征哪些聚集的蛋白质种类是 与每种疾病的不同阶段相关，将大大促进更好的发展， 诊断和治疗策略。我们已经生成了几种表征良好的试剂 特异性识别不同的Abeta和a-syn聚集种类， 证明了试剂识别发生在来自疾病组织中的聚集物质， 但不是健康的大脑，并且试剂也可以具有疾病特异性。这里 我们将开发和测试类似的试剂，用于检测存在于 AD脑组织

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. Since 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.