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