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Conformational heterogeneity and alpha-sheet: Determinants of toxicity in Abeta variants

构象异质性和 α-片层：Abeta 变体毒性的决定因素

基本信息

批准号：
10612839
负责人：
VALERIE D DAGGETT
金额：
$ 62.34万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612839
关键词：
Adopted Affect Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Amyloidosis Animal Model Behavior Binding Biological Biological Assay Biological Models Cell model Cells Cerebrospinal Fluid Circular Dichroism Electrophoresis Electrophysiology (science)Event Heterogeneity Human Immobilization In Vitro Libraries Liquid substance Maps Measurement Methodology Methods Microfluidics Modeling Molecular Conformation Molecular Sieve Chromatography Molecular Weight Monitor Mus Nature Patients Peptides Preparation Process Property Proteins Reagent Role Sampling Site Spectrum Analysis Standardization Stretching Structure System Technology Toxic effect Variant Vertebral column Work abeta oligomer amyloid formation amyloid peptide amyloid structure amyloidogenesis conformer cytotoxicity design experimental study in vivo inhibitor molecular dynamics monomer mutant neuroblastoma cell neuroinflammation novel novel strategies protein data bank simulation

项目摘要

Amyloid diseases involve conformational changes and aggregation of normally soluble peptides and proteins. As these proteins change begin to misfold and aggregate they pass through a toxic soluble oligomer stage and then they ultimately form insoluble fibrils. We have spent many years characterizing the early events in this progression, and have observed a common structure form among multiple amyloid-associated peptides and proteins despite distinct primary and tertiary structure. The structure we “discovered”, which we call α-sheet, while rare in normal proteins, has been observed experimentally, and short stretches of α-strand are present in the Protein Data Bank. We embarked on an endeavor to design and evaluate small peptides with complementary structures, also α-sheets, and their ability to inhibit amyloid formation in these systems. These de novo designed peptides inhibit the aggregation of multiple unrelated amyloid systems, indicating that we are targeting a generic structure. When immobilized, these designs also selectively bind the toxic oligomeric forms of these amyloid proteins over the monomers or fibrils. Here we propose to extend these studies by investigating whether α-sheet forms during amyloidogenesis of Abeta variants associated with Alzheimer's disease. The effects of targeting the toxic oligomers with de novo α-sheet designs will then be evaluated in vitro, in neuroblastoma cells, and in different, more biologically relevant systems.

淀粉样蛋白疾病涉及正常可溶性多肽和蛋白质的构象改变和聚集。