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: 10706566
• 负责人: Charles G. Glabe
• 金额: $ 108.96万
• 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/10706566
• 关键词: Adopted; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Basic Science; Binding; Biological; Brain; Cryoelectron Microscopy; Data; Development; Diagnosis; Disease; Dyes; Economics; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Genetic Polymorphism; Goals; Health; 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; Reaction; 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 accumulation; abeta oligomer; amyloid imaging; amyloid structure; analytical tool; beta pleated sheet; disorder subtype; familial Alzheimer disease; fluorophore; 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 阿尔茨海默氏病（AD）目前是一种无法治愈的神经退行性疾病，影响超过3500万人 全球，包括美国540万个人，每分钟都会诊断出一个新病例。发生淀粉样蛋白 通常是多种神经退行性疾病（例如AD和Desire）的关键病理特征 30年的深入研究，有关发病机理的重要性，机制和作用的重要问题 淀粉样蛋白仍未解决。由于淀粉样蛋白Aß在家族性AD中的含义很大，所以 淀粉样蛋白聚集体的制剂（低聚物，原纤维）已在超过100,000张出版物中出现 过去30年。在许多情况下，相互矛盾，矛盾和不可再生的数据使基本的数据混淆了 发病机理的机制。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，导致发现淀粉样结构高度多态与相同蛋白 序列采用不同的beta表折叠。此外，不同的结构似乎与不同的结构相关 疾病亚型，表明结构变化在发病机理中起作用。这种多态性和 结构性异质性也可能基本的不可补发性和矛盾的结果困扰着淀粉样蛋白 研究。这表明对准备良好的标准化协议的迫切需要进行准备 不同类型的淀粉样蛋白Aß聚集体和试剂，以验证这些制剂并专门识别 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角色 淀粉样蛋白在疾病发病机理中的机制。因此，该资源计划的总体目标是 建立用于开发试剂和协议的源网络，用于生产，标准化， 表征，淀粉样蛋白低聚物和原纤维的身份验证以及将这些材料传播到 调查人员。