Aminergic Function in Brain Aging and Alzheimer's Disease

描述（由申请人提供）：该计划项目资助的重点是了解大脑中的生理和生化变化，这些变化是衰老和阿尔茨海默病期间认知变化的基础。有几个主题贯穿于整个计划项目。一个主要的主题是研究氧化应激和炎症在衰老中的作用。在大脑中有2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）和胶质细胞。所有项目都将从不同的角度研究这个问题，例如项目5、3和1将研究一只线粒体（mt）DNA聚合酶有缺陷的小鼠，这些小鼠显示出早衰的迹象。补助金的第二个重点是研究小胶质细胞功能的各个方面，作为ROS和RNS的来源，以及神经退行性疾病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，从经典激活状态到替代激活状态。该应用的目标之一是了解小胶质细胞表型的动态以及对CNS功能和AD进展的潜在影响。所有项目都将研究小胶质细胞的功能。贯穿整个计划项目的最后一个主题是单胺（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的作用的一个新的方面检查在这个更新是蓝斑（LC）在衰老和疾病中的神经保护作用。包括AD在内的许多神经退行性疾病都有LC神经元丢失作为疾病进展的早期方面。已经表明，LC-NE神经元在保护免受诸如神经炎症和氧化应激的损伤中发挥特定作用。这个想法将在项目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.