Shared resource to develop tools and reagents to study structural polymorphisms in Abeta amyloid aggregates in AD

共享资源开发工具和试剂来研究 AD 中 Abeta 淀粉样蛋白聚集体的结构多态性

• 批准号: 10549101
• 负责人: Charles G. Glabe
• 金额: $ 126.52万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549101
• 关键词: Adopted; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Basic Science; Binding; Biological; Brain; Conflict (Psychology); Cryoelectron Microscopy; Data; Development; Diagnosis; Disease; Dyes; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Genetic Polymorphism; Goals; Heterogeneity; Human; In Vitro; Individual; Methods; Molecular Conformation; Monoclonal Antibodies; Nature; Neurodegenerative Disorders; Pathogenesis; Pathologic; Pathologist; Peptides; Persons; Play; Polymorph; Population; Preparation; Production; Property; Protocols documentation; Publications; Reagent; Recombinants; Reproducibility; Research; Research Personnel; Resource Sharing; Resources; Role; Sampling; Series; Serum; Source; Stains; Standardization; Structural Biologist; Structure; Testing; Time; Transgenic Organisms; Variant; abeta oligomer; amyloid imaging; amyloid structure; analytical tool; base; beta pleated sheet; disorder subtype; familial Alzheimer disease; fluorophore; health economics; in vivo; interest; monomer; structural biology; tool

Project Abstract Alzheimer’s disease (AD) is currently an incurable neurodegenerative disease that affects over 35 million people worldwide, including 5.4 million individuals in the USA with a new case diagnosed every minute. Amyloids occur commonly as key pathological features in a wide variety of neurodegenerative diseases such as AD and despite 30 years of intensive research, important questions about the significance, mechanisms and role in pathogenesis of amyloids remain unresolved. Because of the strong implication of amyloid Aß peptide in familial AD, preparations of amyloid aggregates (oligomers, fibrils) have been featured in over 100,000 publications over the past 30 years. In many cases, conflicting, contradictory and non-reproducible data obfuscate the underlying mechanisms of pathogenesis. Advances in structural biology have established the structures of several distinct types of amyloid, leading to the discovery that amyloid structures are highly polymorphic with the same protein sequence adopting distinct beta sheet folds. Moreover, different structures seem to correlate with different disease subtypes, indicating that structural variation plays a role in pathogenesis. This polymorphism and structural heterogeneity may also underly the irreproducibility and conflicting results that have plagued amyloid research. This suggests a critical need for well-characterized, standardized protocols for the preparation of different types of amyloid Aß aggregates and reagents to authenticate these preparations and specifically identify and quantify these polymorphs in vitro and in brain in order to support basic research to understand the roles and mechanisms of amyloids in disease pathogenesis. Therefore, the overall goal of this resource initiative is to establish a source network for the development of reagents and protocols for the production, standardization, characterization, authentication of amyloid oligomers and fibrils and the dissemination of these materials to investigators.

项目摘要 阿尔茨海默病 (AD) 目前是一种无法治愈的神经退行性疾病，影响着超过 3500 万人 全球范围内，包括美国 540 万人，每分钟诊断出一个新病例。淀粉样蛋白出现 通常是 AD 等多种神经退行性疾病的关键病理特征，尽管 30年深入研究，发病机制中的意义、机制和作用的重要问题 淀粉样蛋白的问题仍未得到解决。由于淀粉样 Aß 肽在家族性 AD 中具有重要意义， 淀粉样蛋白聚集体（寡聚物、原纤维）的制剂已在超过 100,000 种出版物中得到专题报道 过去30年。在许多情况下，相互冲突、矛盾和不可重现的数据混淆了底层数据 发病机制。结构生物学的进步已经建立了几种不同的结构 淀粉样蛋白的类型，导致发现淀粉样蛋白结构与相同的蛋白质具有高度多态性 采用不同的β折叠的序列。此外，不同的结构似乎与不同的 疾病亚型，表明结构变异在发病机制中发挥作用。这种多态性和 结构异质性也可能是困扰淀粉样蛋白的不可重复性和相互矛盾的结果的原因 研究。这表明迫切需要特征明确的标准化方案来制备 不同类型的淀粉样蛋白 Aß 聚集体和试剂来验证这些制剂并特异性识别 并在体外和大脑中量化这些多晶型物，以支持基础研究以了解其作用 淀粉样蛋白在疾病发病机制中的作用和机制。因此，该资源计划的总体目标是 建立试剂和方案开发的来源网络，用于生产、标准化、 淀粉样蛋白寡聚物和原纤维的表征、鉴定以及这些材料的传播 调查人员。