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: 9672801
• 负责人: Christopher P Jaroniec
• 金额: $ 396.94万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9672801
• 关键词: Alzheimer' s Disease; Amides; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Biochemical; Biological; Biological Assay; Biophysics; Brain; Brain Pathology; Cell Culture Techniques; Cell Death; Coupled; Data; Deposition; Deuterium; Development; Disease; Genetic Polymorphism; Heterogeneity; Histidine; Human; Hydrogen; Hydroxyl Radical; Immunoassay; Impaired cognition; In Vitro; Individual; Isotope Labeling; Link; Literature; Mass Spectrum Analysis; Measurement; Methods; Molecular; Molecular Conformation; NMR Spectroscopy; Neurons; Particle Size; Pathogenesis; Pathogenicity; Pathology; Peptide Hydrolases; Phenotype; Principal Investigator; Prions; Property; Reaction; Recombinants; Reporting; Research; Resolution; Role; Sampling; Structure; Structure-Activity Relationship; Sucrose; Testing; Toxic effect; Transgenic Mice; Vertebral column; base; brain tissue; disease phenotype; experimental study; familial Alzheimer disease; high throughput analysis; hyperphosphorylated tau; insight; interdisciplinary approach; molecular marker; novel diagnostics; novel therapeutics; predictive marker; prion hypothesis; prion-like; sedimentation velocity; solid state nuclear magnetic resonance; tau Proteins; tau aggregation; tau conformation

The deposition of aggregated amyloid beta (Aβ) and hyperphosphorylated tau proteins is directly associated with cell death and propagation of brain pathology in sporadic as well as familial forms of Alzheimer's disease (AD). The long-term objective of this research is to define the molecular mechanism responsible for diverse phenotypes and progression rates in AD, and to explore the role of structural polymorphism of Aβ and tau aggregates as a potential determinant of phenotypic variability of the disease. To this end, we propose an integrated multidisciplinary approach involving three principal investigators with complementary expertise. Our key specific objectives are to delineate the AD phenotype-dependent structural organization of Aβ and tau aggregates, establish structure/function relationship, and identify key structural attributes that control distinct pathogenic potential of prion-like strains of Aβ amyloid fibrils and tau filaments. In the brain tissue from phenotypically distinct cases of sporadic and familial AD, we will perform strain-typing of Aβ and tau aggregates using approaches that were developed and validated in prion research. Furthermore, we will characterize the overall structural differences between brain-derived Aβ and tau aggregates corresponding to different AD phenotypes using mass spectrometry-based methods and assess their seeding (replication) potency, an in vitro attribute that relates to the progression rate of disease. Finally, we will obtain high- resolution insight into the structure of in vitro generated high-fidelity replicas of brain-derived Aβ and tau filaments corresponding to distinct phenotypes of AD using solid-state NMR spectroscopy. Establishing the relationship between specific structural features of Aβ and tau strains should uncover critical aspects of the pathogenesis in distinct forms of AD, key factors responsible for very rapid rate of cognitive decline in significant subset of AD, and test the hypothesis that prion-like strains are responsible for phenotypic diversity and progression rate. This insight is critical for efforts to develop molecular markers that predict progression and phenotype of AD and ultimately for novel therapeutic strategies.

聚集的淀粉样β蛋白(Aβ)和过度磷酸化的tau蛋白的沉积直接相关 散发性和家族性阿尔茨海默病的细胞死亡和脑病理传播 疾病(AD)。这项研究的长期目标是确定导致 阿尔茨海默病的不同表型和进展率，以及Aβ结构多态性的作用 而tau聚集体是疾病表型可变性的潜在决定因素。为此，我们 提出一种综合的多学科方法，包括三个主要调查人员，并相互补充 专业知识。我们的主要具体目标是描绘AD表型依赖的结构组织 β和tau聚合体，建立结构/功能关系，并确定关键的结构属性， 控制A、β、淀粉样纤维和tau细丝的Pron样菌株的不同致病潜能。在大脑中 来自不同表型的散发性和家族性AD患者的组织，我们将进行Aβ和 Tau聚合体使用在普恩研究中开发和验证的方法。此外，我们还将 表征脑源性Aβ和tau聚集体之间的总体结构差异 使用基于质谱学的方法识别不同的AD表型，并评估它们的种子(复制) 效力，一种与疾病进展速度有关的体外属性。最终，我们将获得高- 对体外产生的脑源性Aβ和tau的高保真复制品结构的分辨率洞察 使用固态核磁共振波谱，对应于AD的不同表型的细丝。建立 Aβ株和tau株特定结构特征之间的关系应该揭示 不同形式阿尔茨海默病的发病机制，导致认知功能减退速度非常快的关键因素 AD的重要子集，并检验普鲁恩样菌株负责表型的假设 多样性和进步率。这一洞察力对于开发能够预测 阿尔茨海默病的进展和表型，并最终用于新的治疗策略。