Aminergic Function in Brain Aging and Alzheimer's Disease

描述(由申请者提供)：本项目资助的重点是了解在衰老和阿尔茨海默病期间潜在的认知变化的大脑中的生理和生化变化。有几个主题贯穿整个计划项目。一个主要的主题是研究氧化应激和炎症在衰老中的作用。大脑中有两种主要的活性氧(ROS)和活性氮(RNS)来源，它们来自神经胶质细胞(主要是小胶质细胞)和线粒体。所有的项目都将从不同的角度研究这个问题，例如项目5、3和1将检查一只线粒体(MT)DNA聚合酶缺陷的小鼠，这些小鼠显示出过早衰老的迹象。拨款的第二个重点是研究小胶质细胞作为ROS和RNS来源的功能以及神经退化的其他生物触发因素。越来越多的证据表明，小胶质细胞在激活状态下具有多种表型，从经典的激活状态到另一种激活状态。该应用的目的之一是了解小胶质细胞表型的动力学及其对中枢神经系统功能和AD进展的潜在影响。所有项目都将检查小胶质细胞的功能。贯穿整个计划项目的最后一个主题是单胺的作用，特别是去甲肾上腺素(NE)在与年龄相关的中枢神经系统功能下降中的作用的持续主题。NE在这种更新中作用的一个新的方面是蓝斑(LC)在衰老和疾病中的神经保护作用。包括阿尔茨海默病在内的许多神经退行性疾病都有LC神经元的丢失，这是疾病进展的早期方面。已有研究表明，LC-NE神经元在抵抗神经炎症和氧化应激等损伤方面发挥着特殊的作用。这一想法将在项目4以及项目1、3和5中具体阐述。

DESCRIPTION (provided by applicant): This Program Project Grant is focused on understanding physiological and biochemical alterations in the brain underlying changes in cognition during aging and Alzheimer's disease. There are several themes that weave throughout the Program Project. A major theme is to examine the role of oxidative stress and inflammation in aging. There are 2 major sources of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the brain and these are from the glia (primarily the microglia) and the mitochondrion. All projects will examine this question from varying angles, for example projects 5, 3,and 1 will examine a mouse with defective mitochondrial (mt) DNA polymerase that show signs of premature aging. A second focus of the grant is to examine aspects of microglial function as a source of ROS and RNS as well as other biological triggers of neurodegeneration. There is increasing evidence that microglia have multiple phenotypes in the activated state ranging from classical activation states to an alternative activation state. One of the goals of the application is to understand the dynamics of the phenotype of microglia and the potential influence on CNS function and AD progression. All projects will examine microglial function. The final theme that weaves throughout the Program Project is a continuing theme of a role for monoamines, and specifically norepinephrine (NE) in age-related declines in CNS function. A new aspect of the role of NE examined in this renewal is the neuroprotective role of the locus coeruleus (LC) in aging and disease. Many neurodegenerative diseases including AD share a loss of LC neurons as an early aspect of disease progression. It has been suggested that LC-NE neurons play a specific role in protection against insults such as neuroinflammation and oxidative stress. This idea will be specifically addressed in Project 4 as well as Projects 1, 3, and 5.