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的共同点，包括阿尔茨海默氏病（AD），Lewy身体痴呆症（LBD）和帕金森氏病（PD）等。虽然每种疾病主要与特定蛋白的聚集有关；带有AD的β-淀粉样蛋白（ABETA），带有AD和其他tauopathies，具有PD和LBD的α-突触核蛋白（A-SYN），多种蛋白质可能会错误地折叠式脑组织和治疗策略。尽管所有这些蛋白质都可以形成纤维骨料，但它们也可以形成多种 不同的较小的可溶骨料结构。研究表明小型可溶性蛋白 骨料形式是各种疾病中相关的有毒物种，而不是作为诊断标志的原纤维骨料。这些蛋白质中每种蛋白质的各种不同的中间寡聚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产生不同的毒性作用，并且可能优先针对不同类型的细胞。由一种蛋白质（例如ABETA）引起的SINC细胞应激很可能导致其他蛋白质（如Tau和A-Syn）的折叠和聚集，应预期在不同疾病中存在多种错误折叠的蛋白质。因此，表征哪种综合蛋白质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发展。我们产生了几种特征性的试剂，这些试剂特异性地识别了不同的Abeta和A-Syn种类，并证明这些试剂识别出从患病的大脑中发生的组织中发生的聚集物种，但不健康的大脑，并且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，以检测AD脑组织中存在的特定形式的TAU。