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REPURPOSING PRION PROTEINS AS TRANSLATIONAL AMYLOID-TARGETING THERAPEUTICS FOR ALZHEIMER'S DISEASE

重新利用朊病毒蛋白作为阿尔茨海默病的翻译淀粉样蛋白靶向疗法

基本信息

批准号：
10187480
负责人：
Zachary Alan Levine
金额：
$ 12.73万
依托单位：
YALE UNIVERSITY
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：
2020-06-15 至 2022-06-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187480
关键词：
Affect Affinity Alanine Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Amino Acids Amyloid Amyloid Fibrils Amyloid beta-Protein Animal Model Binding Binding Proteins Binding Sites Biological Assay Biological Models Biomimetics Biophysics Blood - brain barrier anatomy Brain Cells Chemicals Chromatography Complex Dementia Dot Immunoblotting Educational workshop Enzyme-Linked Immunosorbent Assay Follow-Up Studies Goals Heterogeneity Human Immersion Immunoassay Impaired cognition Impairment In Vitro Joints Laboratories Length Ligand Binding Link Lipids Liquid substance Measures Mediating Membrane Proteins Mentors Methodology Methods Modeling Molecular Molecular Conformation Molecular Sieve Chromatography NMR Spectroscopy Nerve Degeneration Neurodegenerative Disorders Neurons Noise Optics Pathologic Pathway interactions Peptide aptamers Peptides Physiological PrP Prion Diseases Property Protein Binding Domain Proteins Protocols documentation Rattus Research Resources Sampling Scanning Senile Plaques Severities Severity of illness Side Signal Transduction Spectrum Analysis Speed Structural Models Structure Synapses System Tertiary Protein Structure Testing Thermodynamics Tissues Toxic effect Translations Water abeta oligomer abeta toxicity age related amyloid formation aptamer base biophysical analysis clinically relevant cost effective cytotoxicity design effectiveness evaluation efficacy evaluation experimental study genome wide screen in vivo meetings molecular dynamics monomer next generation protein complex relating to nervous system screening simulation synaptic function targeted treatment tau Proteins tau aggregation therapeutic target

项目摘要

PROJECT SUMMARY Cognitive decline in Alzheimer’s Disease (AD) and many other age-related dementias have long been associated with the presence of insoluble amyloid plaques that disrupt normal synaptic functioning. However, more recent studies have revealed that synapse impairment from AD is much more potently associated with soluble amyloid-beta oligomers (abo), rather than from insoluble fibrils. Soluble oligomers are structurally irregular and promiscuously bind to membrane proteins, thereby dysregulating downstream amyloid assemblies such as tau. These properties, unfortunately, have also made it difficult to experimentally characterize abo, since oligomeric states can be transient or otherwise observed as noise. Multiple genome-wide screening methods have identified cellular prion protein (PrPc) as a putative target of abo, and subsequent studies have confirmed a pathophysiological pathway in AD involving abo-PrPc binding. Interestingly, ab monomers and insoluble fibrils do not bind to PrPc, thus the binding domain of PrPc can be exploited in peptide aptamers to target and stabilize abo. Here, we seek to utilize these interactions by designing biomimetic PrPc peptides that complex soluble abo. Molecular simulations and amyloid-characterizing experiments will be combined to optimize aptamer-abo interactions in order to abrogate binding of abo to PrPc. While aptamers are unlikely to serve as an AD therapeutic, amyloid-targeting PrPc peptides can guide the construction of next-generation agents that cross the blood-brain barrier and potently inhibit the toxicity of abo. Similarly, identification of abo by aptamers can potentially enable the tracking of soluble oligomers through fluorescent tagging during the formation of insoluble fibrils. Given that there are few, if any methodologies to target abo, this proposal would seek to isolate soluble oligomers and identify the limitations of their interactions with membrane proteins. In order to synergistically combine molecular dynamics simulations with experiments, mentoring will be carried out on the use of NMR spectroscopy, chromatography, and ligand-binding assays to measure oligomer structure, size, and the ability to bind PrP proteins, respectively. Mentoring will include regular meetings, coursework, workshops, and immersion in the laboratory of the primary mentor. Additionally, this study will seek to bridge basic biophysical research with clinically-relevant systems through the translation of model aptamers from simulations into experiments. Results will be connected to and interpreted in the context of Alzheimer’s Disease. The protocols and products developed as a result of this study will subsequently inform follow-up studies of soluble amyloid toxicity in live cells, with extensions to multiple neurodegenerative diseases.

项目总结