Nanobodies selective for oligomeric Tau species isolated from AD brain

对从 AD 脑中分离出的寡聚 Tau 物种具有选择性的纳米抗体

• 批准号: 8633097
• 负责人: MICHAEL R SIERKS
• 金额: $ 23.83万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633097
• 关键词: Age; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Binding; Biological Markers; Brain; Cells; Cellular Stress; Dementia; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Donkeys; Early Diagnosis; Event; Generations; Goals; Human; Huntington Disease; Immunoglobulin Fragments; In Vitro; Lead; Lewy Body Dementia; Monitor; Morphology; Neurodegenerative Disorders; Onset of illness; Parkinson Disease; Patients; Post-Translational Protein Processing; Process; Proteins; Reagent; Sampling; Serum; Source; Specificity; Staging; Structure; Tauopathies; Testing; Therapeutic; Tissue Sample; Tissues; Toxic effect; Variant; alpha synuclein; base; brain tissue; cell type; direct application; disorder control; extracellular; human Huntingtin protein; human tissue; in vivo; nanobodies; novel; protein aggregate; protein aggregation; protein misfolding; protein purification; public health relevance; tau Proteins; tau aggregation; tau-1; therapeutic target; tool; treatment strategy

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.

蛋白质错误折叠和聚集是许多神经退行性变背后的共同线索 阿尔茨海默病(AD)、路易体痴呆(LBD)和帕金森氏症等疾病 疾病(PD)等。虽然每种疾病都主要与聚集在一起 一种特定的蛋白质；患有AD的β-淀粉样蛋白(ABETA)，患有AD的tau和其他tau病，α- 突触核蛋白(a-syn)与PD和LBD，多个蛋白质可能错误折叠和聚集在 脑组织复杂的诊断和治疗策略。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更小的可溶聚集体结构 也是。研究表明，小的可溶蛋白质聚集体形式是相关的毒性 各种疾病中的物种，而不是用作诊断的纤维集合体 这是个标志。这些蛋白质中的每一种的各种不同的中间寡聚形式可以 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， 并且可以优先以不同类型的单元为目标。由于错误折叠引起的细胞应力 而一种蛋白质(如abeta)的聚集很可能导致错误折叠和聚集 其他蛋白质如tau和a-syn，在不同的蛋白质中存在多个错误折叠的蛋白质 疾病应该是可以预料到的。因此，表征哪些聚集蛋白质物种是 与每种疾病的不同阶段相关联将极大地促进更好的 诊断和治疗策略。我们已经产生了几种具有良好特性的试剂 专门识别不同聚集的abeta和a-syn物种，并具有 证明这些试剂可以识别疾病组织中出现的聚集物种 大脑，但不是健康的大脑，这些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来检测存在于 AD脑组织。