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: 8741902
• 负责人: MICHAEL R SIERKS
• 金额: $ 19.31万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741902
• 关键词: Age; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Asses; Binding; Biological Markers; Brain; Cells; Cellular Stress; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Event; Frontotemporal Dementia; 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

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.

描述（由申请人提供）：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。虽然每种疾病主要与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蛋白病、α-突触核蛋白（a-syn）与PD和LBD，但一种以上的蛋白质可能在脑组织中错误折叠和聚集，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蛋白质。 不同的小的可溶性聚集体结构。研究表明，小分子可溶性蛋白 聚集体形式是各种疾病中的相关有毒物质，而不是作为诊断标志的纤维状聚集体。这些蛋白质中的每一种的多种不同的中间寡聚体形式可以在体外和体内存在，并且不同的聚集体形式可以对细胞具有不同的毒性作用，并且可以优先靶向不同类型的细胞。由于由一种蛋白质如abeta的错误折叠和聚集诱导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，因此在不同疾病中存在多种错误折叠蛋白是可以预期的。因此，表征哪种聚集蛋白种类与每种疾病的不同阶段相关将极大地促进更好的诊断和治疗策略的开发。我们已经产生了几种充分表征的试剂，其特异性地识别abeta和a-syn的不同聚集种类，并且已经证明所述试剂识别来自患病脑而不是健康脑的组织中出现的聚集种类，并且所述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，用于检测AD脑组织中存在的特定形式的tau。