Cellular trafficking of pathogenic Abeta seeds in vitro and in vivo

致病性 Abeta 种子的体外和体内细胞运输

基本信息

批准号：
8319398
负责人：
Ranjita S Betarbet
金额：
$ 18.04万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319398
关键词：
Abdominal Cavity Address Age Aging Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Amyloid deposition Amyloidosis Bacteria Blood Circulation Brain Brain Diseases Cell Culture Techniques Cells Cerebrum Data Degenerative Disorder Dementia Deposition Disease Elderly Event Goals Greater sac of peritoneum Health Human In Vitro Infusion procedures Ingestion Injection of therapeutic agent Intraperitoneal Injections Mediating Modeling Molecular Mononuclear Mus Nerve Degeneration Neurodegenerative Disorders Organism Pathogenesis Pathologic Pathway interactions Patients Peptides Personal Satisfaction Phagocytes Phagocytosis Play Population Precipitating Factors Process Proteins Reporting Research Role Seeds Seminal Transgenic Mice Virus Work hazard in vitro Model in vivo innovation insight macrophage mouse model novel novel therapeutic intervention prion-like protein aggregate protein aggregation residence trafficking vector

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in aging humans, currently afflicting approximately 5 million Americans. Research recently has shown that an important feature of AD is the abnormal accumulation of specific proteins in the brain, and that the aggregation of the protein A¿ is a primary event. However, how this process of aggregation is initiated, and how the aggregates spread from one region to another, remains uncertain. The goal of our research is to understand the cellular and molecular processes that initiate the pathogenesis of AD. Our previous studies found that the deposition of A¿ can be induced, or seeded, in the brains of transgenic mouse models of AD by the infusion of dilute, A¿-rich brain extracts containing aggregated A¿. Very recently we found that A¿ aggregation can be seeded by injections of A¿-rich brain extracts into the abdominal cavity of mice. Preliminary data implicate mononuclear phagocytes (macrophages) as the vectors of the seeds, in that A¿-seed- laden macrophages enter the circulation following the intraperitoneal injection of seed. However, direct evidence for the cellular transport of the seeds into the brain is lacking. The objective of this project is to clarify the role of macrophages in disseminating the seeds for A¿ aggregation using a transgenic mouse model and in vitro models of the processing of seeds by macrophages. In the vast majority of AD cases, the factors that precipitate protein aggregation remain unknown. Understanding the cellular mechanisms underlying induced A¿ aggregation and spread could eventually point the way to new therapies for Alzheimer's disease and other debilitating brain disorders of the elderly.

描述（由适用提供）：阿尔茨海默氏病（AD）是衰老人类痴呆的最常见原因，目前遭受了约500万美国人的困扰。最近的研究表明，AD的一个重要特征是大脑中特定蛋白质的异常积累，而蛋白质a。的聚集是主要事件。但是，如何启动这种聚合过程，以及聚合如何从一个区域传播到另一个区域，仍然不确定。我们研究的目的是了解启动AD发病机理的细胞和分子过程。我们先前的研究发现，通过输注稀释的AD的转基因小鼠模型的大脑可以诱导A的沉积物，或者播种。最近，我们发现可以通过注射富含a的脑提取到小鼠的腹腔中来播种。初步数据暗示单核吞噬细胞（巨噬细胞）是种子的载体，因为在腹膜内注射种子后，A seed -seed -Laden巨噬细胞进入了循环。但是，缺乏向种子进入大脑的细胞转运的直接证据。该项目的目的是阐明巨噬细胞在使用转基因小鼠模型和巨噬细胞处理种子加工的体外模型中散布种子以进行A聚集的作用。在绝大多数AD病例中，沉淀蛋白质聚集的因素仍然未知。了解诱导A聚集和扩散的细胞机制最终可能会为阿尔茨海默氏病新疗法和其他较老的脑疾病的新疗法指向。