Structural determinants of amyloid strain heterogeneity in distinct phenotypes of Alzheimer's disease

阿尔茨海默病不同表型中淀粉样蛋白菌株异质性的结构决定因素

• 批准号: 10375763
• 负责人: Christopher P Jaroniec
• 金额: $ 40.07万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375763
• 关键词: Administrative Supplement; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Area; Award; Brain; Brain Pathology; Cell Death; Deposition; Development; Disease; Environment; Foundations; Frontotemporal Dementia; Future; Goals; Heterogeneity; Lead; Liquid substance; Neurodegenerative Disorders; Parents; Pathogenicity; Pathologic; Phase; Phenotype; Physical condensation; Process; Property; Proteins; Research; Role; Structure; hyperphosphorylated tau; insight; novel therapeutic intervention; tau Proteins; tau aggregation

The deposition of aggregated hyperphosphorylated tau protein in brain is directly associated with cell death and propagation of brain pathology in Alzheimer's disease and several other neurodegenerative diseases, including frontotemporal dementia. The major goal of the parent award RF1 AG 061797 is to elucidate the relationship between structural properties of tau and Aβ aggregates and phenotypic variability of Alzheimer's disease and related disorders. An important recent development is the finding that, akin to some other proteins involved in neurodegenerative diseases, tau can undergo liquid-liquid phase separation, forming condensates in which protein concentration is extremely high. The environment of these condensates may have a major impact on the aggregation properies of tau, contributing to the pathogenic process. The purpose of this Administrative Supplement is to expand the scope of studies in the parent award into this rapidly emerging area of research, with the main specific objective to elucidate the mechanisms of tau liquid-liquid phase separation and the role of different types of interactions in this process. The insights gained in this research should provide a necessary foundation for future studies aimed at understanding the intricate role of liquid-liquid phase separation in pathological aggregation of tau in Alzheimer's disease and related disorders.

聚集的过度磷酸化tau蛋白在脑中的沉积与细胞死亡直接相关， 阿尔茨海默病和其他几种神经退行性疾病的脑病理学传播，包括 额颞叶痴呆父奖项RF 1 AG 061797的主要目标是阐明 tau和Aβ聚集体的结构特性与阿尔茨海默病的表型变异性之间的关系， 相关疾病。最近的一个重要进展是发现，类似于其他一些参与蛋白质， 在神经退行性疾病中，tau可以经历液-液相分离，形成冷凝物，其中 蛋白质浓度非常高。这些冷凝物的环境可能对 tau的聚集特性，有助于致病过程。本行政管理的目的 补充是为了扩大研究范围的母奖进入这一迅速新兴的研究领域， 主要的具体目的是阐明tau液-液相分离的机制和 在这个过程中的不同类型的相互作用。在这项研究中获得的见解应该提供一个必要的 为今后的研究奠定了基础，旨在了解液-液相分离在 阿尔茨海默病和相关病症中tau的病理性聚集。