Molecular pathways leading to neurodegeneration in vivo

导致体内神经变性的分子途径

• 批准号: 8887495
• 负责人: Brian J Bacskai
• 金额: $ 50.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/8887495
• 关键词: Affect; Age; Alzheimer' s Disease; 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; Cessation of life; Chemicals; Clinic; Clinical; Communities; Complex; Consensus; Dementia; Disease; Disease Progression; Elderly; Etiology; Event; Functional disorder; Generations; Genetic; Goals; Health; Homeostasis; Image; Individual; Intervention; Lead; Life; Link; Measures; Microscopy; Mitochondria; Modeling; Molecular; Molecular Target; Monitor; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Neurosciences; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patients; Peptides; Preparation; Process; Production; Protective Agents; Reaction; Reactive Oxygen Species; Research; Risk; Senile Plaques; Sequence Determination; Structure; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Time Factors; Toxic effect; Transgenic Mice; Transgenic Model; Transgenic Organisms; Translating; Vertebral column; Work; amyloid pathology; amyloid peptide; antioxidant therapy; base; cellular targeting; cytotoxic; effective therapy; functional outcomes; imaging probe; in vivo; insight; intravital imaging; mitochondrial dysfunction; molecular/cellular imaging; mouse model; network dysfunction; neurodegenerative phenotype; neuron loss; prevent; protein aggregate; protein misfolding; public health relevance; tool; treatment strategy

 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）：阿尔茨海默病是老年人痴呆症的主要原因，由于风险个体的数量正在迅速增加，AD代表了一个主要的健康危机。在这一点上，虽然出现了一些关键的见解和临床工具，但仍然没有有效的治疗方法来预防或逆转这种疾病。AD的遗传学已经导致了疾病进展的简单和合理的假设：淀粉样蛋白-β 2（一种已知的细胞毒性肽，其形成小的可扩散的和大的不溶性聚集体）导致神经变性和AD。这个简单的假设导致了大量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，并且在使用的每个基于细胞的测定中绝对导致细胞毒性。合成淀粉样蛋白制剂的滥用使该领域变得混乱，在很大程度上阻碍且无助于AD的研究进展。现在很清楚，疾病的进展是一个复杂得多的过程。AD是一种多因素疾病，必须包括一系列随时间变化的细胞和分子事件。因此，虽然不可能忽视Ablation在某种程度上是疾病的核心，但显然需要确定生理学相关模型中的事件顺序，以确定年龄敏感的治疗策略。疾病进展的其他关键原则也很重要，但尚未明确定义。众所周知，氧化应激、线粒体 改变和钙稳态异常是细胞死亡途径上的关键分子组分。然而，对于这些事件是否与疾病相关、因果关系或反映疾病，尚无共识。因此，我们的目标是系统地评估这些分子和细胞事件的时间序列，在活的大脑中的最彻底的特点转基因小鼠模型的AD，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，告知多因素的治疗策略的基础上的持续时间和进展程度。我们将检验这一假设，即黄芪通过钙稳态异常、活性氧生成和线粒体失调的途径导致神经退行性变。为了验证这一假设，我们将开发工具，使用多光子显微镜在APP小鼠的活脑中对这些终点中的每一个进行成像，这些工具本身将对神经科学界广泛有用。最后，我们将探索干预措施，以确定最终将导致阿尔茨海默病患者治疗的治疗途径。