Molecular pathways leading to neurodegeneration in vivo

导致体内神经变性的分子途径

基本信息

批准号：
9472989
负责人：
Brian J Bacskai
金额：
$ 46.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9472989
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Antibodies Biological Assay Biological Neural Networks Biology Brain Brain imaging Calcium Caspase Cell Death Cell physiology Cells Cellular Structures Cellular biology Central Nervous System Diseases Chemicals Clinic Clinical Communities Complex Consensus Dementia Diffuse Disease Disease Progression Disease model Elderly Etiology Event Functional disorder Generations Genetic Goals Health Homeostasis Image Individual Intervention Lead Link Measures Microscopy Mitochondria Modeling Molecular Monitor Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Neurosciences Outcome Oxidative Stress Pathologic Pathology Pathway interactions Patients Peptides Physiological Preparation Process Production Protective Agents Reaction Reactive Oxygen Species Research Risk Senile Plaques Structure Techniques Testing Therapeutic Therapeutic Intervention Time Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms Translating Vertebral column Work amyloid pathology amyloid peptide antioxidant therapy base cellular imaging cellular targeting cytotoxic effective therapy fluorescence imaging functional outcomes imaging probe in vivo in vivo imaging insight intravital imaging misfolded protein mitochondrial dysfunction molecular imaging molecular targeted therapies mouse model network dysfunction neurodegenerative phenotype neuron loss pathology imaging prevent protein aggregate public health relevance therapeutic candidate tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease is the leading cause of dementia in the elderly, and because the number of at risk individuals is rapidly increasing, AD represents a major health crisis. At this point, while a number of key insights and clinical tools have arisen there are still no effective treatments to prevent or reverse the disease. The genetics of AD have led to a simple and plausible hypothesis of disease progression: amyloid-ß, a known cytotoxic peptide that forms both small diffusible and large insoluble aggregates, leads to neurodegeneration and AD. This simple hypothesis has led to myriad studies using high concentrations of synthetic amyloid peptide that is almost impossible to work with from a chemical biology standpoint, and absolutely leads to cell toxicity in every cell based assay used. Indiscriminate use of synthetic amyloid preparations have confounded the field, for the most part hampering and not helping research progress in AD. It is clear now that the progression of disease is a much more complex process. AD is a multifactorial disease that must include a spectrum of cellular and molecular events that change over time. Therefore, while it is impossible to ignore that Aß is somehow central to the disease, there is a clear need to determine the sequence of events in physiologically relevant models that will identify age sensitive treatment strategies. There are other key tenets of disease progression that are central, but still not clearly defined. It is well established that oxidative stress, mitochondrial alterations, and calcium dyshomeostasis are key molecular components on the pathway to cell death. However, there is no consensus as to whether these events are related, causal, or reflective of the disease. Therefore, we aim to systematically evaluate the temporal sequence of these molecular and cellular events in the living brain of the most thoroughly characterized transgenic mouse models of AD to identify the contribution of these factors, the causality of these factors, and the appropriate timing of these factors in the course of the disease to inform multifactorial therapeutic strategies based on duration and extent of progression. We will test the hypothesis that Aß leads to neurodegeneration through a pathway involving calcium dyshomeostasis, ROS generation, and mitochondrial dysregulation. To test this hypothesis, we will develop tools to image each of these endpoints in the living brain of APP mice using multiphoton microscopy that in and of themselves will be broadly useful to the neuroscience community. Finally, we will explore interventions to identify therapeutic pathways that ultimately will lead to treatments for Alzheimer's disease in patients.

描述（由申请人提供）：阿尔茨海默氏病是老年人痴呆的主要原因，并且由于高危人群的数量正在迅速增加，因此阿尔茨海默氏病代表着一场重大的健康危机。尽管工具已经出现，但仍然没有有效的治疗方法来预防或逆转这种疾病。 AD 的遗传学导致了一种简单而合理的疾病进展假说：淀粉样蛋白-β，一种已知的细胞毒性肽，可形成小的可扩散的和大的不溶性肽。这个简单的假设导致了无数使用高浓度合成淀粉样肽的研究，从化学生物学的角度来看，这几乎是不可能的，并且在所有基于细胞的分析中绝对会导致细胞毒性。合成淀粉样蛋白制剂的使用使该领域感到困惑，在很大程度上阻碍并且无助于 AD 的研究进展，现在很明显，AD 的进展是一个复杂得多的过程，必须包括一系列因素。细胞的因此，虽然不可能忽视 Aß 在某种程度上是该疾病的核心，但显然需要确定生理相关模型中的事件顺序，以确定年龄敏感的其他关键治疗策略。氧化应激、线粒体是疾病进展的核心原则，但尚未明确定义。然而，对于这些事件是否与疾病相关、因果或反映，尚未达成共识。因此，我们的目标是系统地评估这些事件的时间顺序。研究最彻底的 AD 转基因小鼠模型活体大脑中的分子和细胞事件，以确定这些因素的贡献、这些因素的因果关系以及这些因素在疾病过程中的适当时机，从而为多因素治疗策略提供信息基于持续时间和进展程度。我们将检验 Aß 通过涉及钙稳态、ROS 生成和线粒体失调的途径导致神经变性的假设。为了检验这一假设，我们将开发工具，使用多光子显微镜对 APP 小鼠活体大脑中的每个端点进行成像。最后，我们将探索干预措施，最终确定治疗阿尔茨海默病患者的治疗途径。