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（由适用提供）：阿尔茨海默氏病是古老的痴呆症的主要原因，并且由于处于危险的人数正在迅速增加，因此广告代表了重大的健康危机。在这一点上，尽管已经出现了许多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扭转疾病。 AD的遗传学导致了疾病进展的简单且合理的假设：淀粉样蛋白 - β是一种已知的细胞毒性肽，形成了小型扩散和大型不溶性聚集体，导致神经变性和AD。这个简单的假设导致了众多的研究，使用高浓度的合成淀粉样蛋白肽，从化学生物学的角度来看，几乎不可能使用，并且绝对导致每个基于细胞的测定方法中的细胞毒性。合成淀粉样蛋白制剂的不加选择的使用使该领域混淆了，大部分时间都在阻碍，而无助于研究AD的进展。现在很明显疾病的进展是一个更加复杂的过程。 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，尽管不可能忽略Aß在某种程度上是该疾病的核心，但显然需要确定可以识别年龄敏感治疗策略的物理相关模型中事件的顺序。疾病进展的其他关键原则是中心的，但仍未明确定义。众所周知，氧化应激，线粒体 改变，钙嗜瘤是细胞死亡途径上的关键分子成分。但是，对于这些事件是相关，随意还是反映疾病，尚无共识。因此，我们旨在系统地评估最彻底表征的AD的转基因小鼠模型中这些分子和细胞事件的临时序列，以确定这些因素的贡献，这些因素的偶然性以及这些因素在疾病过程中的适当时间，以根据持续时间和进展的程度为多影响的策略提供依据。我们将检验以下假设：Aß通过涉及钙异质症，ROS产生和线粒体功能障碍的途径导致神经退行性。为了检验这一假设，我们将使用多光子显微镜在App Mice的活体大脑中对每个端点进行成像，而这些工具本身将对神经科学群落非常有用。最后，我们将探索干预措施，以确定最终导致患者阿尔茨海默氏病的治疗途径。