Coupling and spread of molecular and functional pathology of Alzheimer's disease

阿尔茨海默病分子和功能病理学的耦合和传播

基本信息

批准号：
10217616
负责人：
Elizabeth A Proctor
金额：
$ 43.8万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217616
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology American Animal Model Animals Attention Autopsy Behavioral Biological Assay Blood Vessels Blood flow Brain Brain region Cell Death Cells Cerebrovascular Circulation Chronology Clinical Communication Computer Models Control Animal Coupling Data Defect Development Diagnosis Diagnostic Disease Disease Progression Disease model Epidemic Event Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Future Goals Guidelines Hybrids Immune Immune System Diseases Immunization Immunologic Markers Impaired cognition Inflammation Inflammatory Link Machine Learning Magnetic Resonance Imaging Maps Measures Medicine Metabolic Metabolic dysfunction Metabolism Mitochondria Modeling Molecular Mus Neurodegenerative Disorders Onset of illness Pathologic Pathologic Processes Pathology Pathway interactions Patients Physiological Pilot Projects Population Positioning Attribute Proteins Publishing Research Personnel Research Project Grants Rest Rodent Structure System Systems Biology Technology Testing Therapeutic Time TimeLine Tissues Travel Work awake behavioral phenotyping brain cell cytokine diagnostic biomarker effective therapy imaging approach interest molecular pathology mouse model neural circuit neural network neuroimaging neuroinflammation neuron loss neurotoxic novel postnatal protein aggregation relating to nervous system spatiotemporal success therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is a progressive and invariably fatal neurodegenerative disease resulting in loss of cognitive and bodily function, and no cure or effective treatment currently exists. While several pathological processes have been implicated in Alzheimer’s disease, including protein aggregation, inflammation, decreased blood flow, and metabolic defects, the exact mechanism of neuronal death and how the disease spreads from one region of the brain to another is unknown. The goal of this research project is to test whether molecular and cellular dysfunction can be transmitted from cell to cell along their pathways of communication in the brain. To achieve this goal, we will first map the functional connectivity between regions of brain in a mouse model of Alzheimer’s disease using resting-state functional magnetic resonance imaging, observe how these connections change over the progression of the disease, and link these functional changes to behavioral phenotypes in animals. We will then profile levels of inflammatory cytokines and metabolites in tissue from several brain regions in these same mice, and observe whether changes in immunometabolic state coincide in time and space with the functional connections measured by MRI. Successful completion of this work will test a potential mechanism of Alzheimer’s disease spreading through the brain, and provide a map of coupling between immune, metabolic, and functional pathology that could open new directions for future development of early disease diagnostics and therapeutic strategies.

项目概要/摘要阿尔茨海默病是一种进行性且总是致命的神经退行性疾病，会导致认知能力丧失和身体功能，目前尚无治愈或有效的治疗方法，但存在几种病理过程。与阿尔茨海默病有关，包括蛋白质聚集、炎症、血流量减少、和代谢缺陷、神经元死亡的确切机制以及疾病如何从某一区域传播这个研究项目的目标是测试分子和细胞是否能将大脑与另一个大脑联系起来。功能障碍可以沿着大脑中的通讯途径从一个细胞传递到另一个细胞来实现。为了实现这一目标，我们将首先绘制阿尔茨海默病小鼠模型中大脑区域之间的功能连接图使用静息态功能磁共振成像来观察疾病，观察这些连接如何变化我们将研究疾病的进展，并将这些功能变化与动物的行为表型联系起来。然后分析这些相同脑区的组织中炎症细胞因子和代谢物的水平小鼠，观察免疫代谢状态的变化在时间和空间上是否与功能状态一致这项工作的成功完成将测试阿尔茨海默病的潜在机制。疾病通过大脑传播，并提供免疫、代谢和功能之间的耦合图病理学可以为早期疾病诊断和治疗的未来发展开辟新方向策略。