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.