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Elucidating the biophysical and biological properties of the p3 fragment in Alzheimer's Disease

阐明阿尔茨海默病中 p3 片段的生物物理和生物学特性

基本信息

批准号：
10065425
负责人：
Ariel Jade Kuhn
金额：
$ 3.95万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-26 至 2022-09-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065425
关键词：
Abeta clearance Adopted Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amino Acids Amyloid Amyloid Fibrils Amyloid beta-Protein Antibodies Apoptosis Binding Biochemical Biological Biological Assay Biophysics C-terminal Calcium Cause of Death Cells Confocal Microscopy Data Disease model Exhibits Exposure to Fluorescein Future Homeostasis Hydrogen Bonding Hydrophobicity Incubated Inflammation Kinetics Label Learning Length Literature Methods Microscopy Modeling Monitor Morphology NOESY Neurodegenerative Disorders Neurons Pathway interactions Peptides Play Positioning Attribute Preparation Process Production Property Protein Isoforms Proteins Reactive Oxygen Species Research Role Senile Plaques Structure Techniques Toxic Actions Toxic effect Variant Work abeta accumulation abeta toxicity amyloid fibril formation amyloid peptide aqueous beta pleated sheet career crosslink enantiomer human old age (65+)improved insight microscopic imaging multidisciplinary peptide P3 self assembly therapeutic target tissue culture uptake

项目摘要

PROJECT SUMMARY Alzheimer’s Disease is the 6th leading cause of death in the U.S, affecting 10% of seniors over the age of 65. Despite the myriad Alzheimer’s Disease therapeutics targeting the production and clearance of the β-Amyloid (Aβ) peptide, an effective cure is yet to be identified. The current, commonly accepted amyloid model of this disease only seeks to understand the properties of two predominant isoforms of Aβ - with 40 or 42 amino acids. However, plaques isolated from the brains of Alzheimer’s patients contain a variety of Aβ peptides and other proteins. The long-term objective of the proposed research is to elucidate the mechanisms by which Aβ and its variants contribute collectively to the pathology of Alzheimer’s Disease. A C-terminal fragment of Aβ, p3, has been described as soluble and void of amyloidogenic properties since its discovery, despite minimal scientific evidence to support this. I propose to synthesize and characterize the aggregation and mechanism of toxicity of p3 to elucidate its role in amyloid fibril formation. My hypothesis is that the p3 fragment forms amyloid fibrils capable of imparting drastic changes on the oligomerization of the well-studied 40 and 42 length Aβ. The current amyloid model can be significantly improved by understanding the collective contribution of all Aβ peptides through their kinetic interactions. Aim I will provide insights on how p3 aggregates into amyloid fibrils and how that pathway deviates from Aβ with the use of kinetic assays, antibodies and photo-induced crosslinking. Aim 2 will create a more heterogenous model for the aggregation of amyloid peptides into fibrils through coincubation and seeding assays with p3 and Aβ. Aim 3 will provide advances in our understanding of how p3 exerts its toxicity on cells and how that pathway differs from that of Aβ. The mechanism of p3 toxicity will be explored with various biorthogonal cellular uptake methods and apoptosis assays. Completing the listed aims will elucidate the role that p3 plays in the kinetics of amyloid plaque formation and cell toxicity. By providing key insights into the aggregation properties and biological activity of p3, the proposed work will clarify how p3 interacts with Aβ. Ultimately, I expect the results to modify and refine the currently accepted amyloid model, providing a more comprehensive understanding of the pathology of Alzheimer’s Disease.

项目总结