Formation and Propagation of Tau Oligomeric Strains in Alzheimer's Disease

阿尔茨海默病中 Tau 寡聚菌株的形成和繁殖

• 批准号: 10448555
• 负责人: Rakez Kayed
• 金额: $ 80.56万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448555
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Area; Biochemical; Biologic Characteristic; Biological; Biology; Biophysics; Brain; Brain region; Cell model; Cellular Assay; Characteristics; Clinical Trials Design; Data; Deposition; Diagnosis; Diagnostic; Disease; Disease Progression; Evaluation; Functional disorder; Future; Genetic; Genotype; Grant; Health; Immunologics; Impact evaluation; In Vitro; Mission; Molecular; Molecular Conformation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome Study; Pathologic; Pathology; Personal Satisfaction; Persons; Polymorph; Prion Diseases; Property; Proteins; Reaction; Recombinants; Reproducibility; Resolution; Role; Sampling; Series; Stains; Structure; Symptoms; Tauopathies; Therapeutic; Toxic effect; United States National Institutes of Health; Variant; base; comorbidity; design; detection method; disease phenotype; improved; in vivo; insight; novel; personalized medicine; personalized therapeutic; protein aggregation; tau Proteins; tau aggregation; therapeutic development

The pathological aggregation of the microtubule-associated protein tau and its subsequent deposition in neurofibrillary tangles (NFTs) are defining histopathological features of Alzheimer’s disease (AD) and many other neurodegenerative disorders. Although accumulated tau protein aggregates in the brain are a consistent hallmark of AD, there is a vast array in the progression rate of disease and diversity in symptoms. An expansive body of evidence demonstrates that AD shares important characteristics with prion diseases in terms of protein aggregation where conformational variants of tau and Aβ can induce templating of aggregation in cell models or in vivo. Recent advances have spurred a series of critical questions as i) how variable tau aggregate strains can be, ii) formation of tau strains with the ability of spreading within the brain regions and induce aggregation of native tau, iii) the propensity of diverse tau strains to precede and accompany other amyloid aggregation. Our central hypothesis is that the biological properties of AD-relevant tau oligomer strains in specific genetic background and mixed protein pathologies are encoded in the structure of these aggregates. Thus, the interplay/competition between distinct tau oligomer strains is a critical determinant in controlling the extent of disease progression and initiating definite toxicity cascades in AD. The identification of the most dominant and latent strains will be crucial for the design of personalized therapeutic strategies by enhancing accurate targeting of the toxic species. This proposal is based on our excellent progress and exciting preliminary data and supported by our competent team and collaborators, will address tau oligomeric strain biology and the unexplored role of domination in oligomer stains, thus regulating disease progression and phenotypes in AD, one of the most relevant contemporary NIH mission areas. The novel insights gained from this study will lead to the future designing of clinical trials and the possibility for personalized medicine.

微管相关蛋白tau及其后续的病理性聚集 神经原纤维缠结(NFT)中的沉积是阿尔茨海默病的组织病理学特征 阿尔茨海默病(AD)和许多其他神经退行性疾病。虽然累积的tau蛋白 大脑中的聚集物是AD的一贯特征，在进展中有大量的阵列 发病率和症状的多样性。大量证据表明AD 在蛋白质聚集方面与普恩病毒疾病有相同的重要特征 Tau和Aβ的构象变体可以在细胞模型或在 活着。最近的进展引发了一系列关键问题，因为i)变量tau是如何聚集的 菌株可以是，ii)形成tau菌株，具有在大脑区域内传播的能力和 诱导天然tau的聚集，III)不同tau菌株的倾向先于和 伴有其他淀粉样蛋白聚集。 我们的中心假设是AD相关tau寡聚体菌株的生物学特性 特定的遗传背景和混合蛋白病理在这些结构中编码 集合体。因此，不同tau寡聚体菌株之间的相互作用/竞争是至关重要的。 控制疾病进展程度和引发明确毒性的决定因素 在公元后出现了级联效应。确定最显性和潜伏性的菌株将是至关重要的 通过加强对毒物的准确靶向设计个性化治疗策略 物种。 这项建议是基于我们出色的进展和令人振奋的初步数据，并得到 我们有能力的团队和合作者，将研究tau寡聚体的生物学和 寡聚体染色中的支配作用未知，从而调节疾病的进展和 AD的表型，当代最相关的NIH任务区之一。新奇的洞察 从这项研究中获得的将导致未来的临床试验的设计和可能性 个性化医疗。