The proposed research meets Research Objective 21, Amyloid Precursor Protein (APP); these are established investigators. The amyloid precursor protein is a ubiquitously expressed, developmentally regulated protein. It is expressed by both neurons and glia. Its function is unknown but its expression appears to be altered in response to injury. The central hypothesis of the proposed studies is that the amyloid precursor protein (APP) is over-expressed by activated glia in areas of damage in the aged brain. This hypothesis is not readily testable in humans because of the static picture derived from post mortem material. In addition, the mouse and rat re poor models for the human because of sequence differences in the amyloid precursor protein and because of the relatively rapid aging process in these species. The aged Octodon degu brain demonstrates amyloid accumulation similar to that found in humans. We predict that the degu will show greater sequence homology to human APPs than does the rat or the mouse. As a consequence, we proposed that the aged degu is a superior model for human aged-related alterations in APP expression with related cognitive decline. The pilot studies proposed here will develop data to support long range studies into the role of alterations in expression of APPs in age-related cognitive decline. The pilot studies proposed here will develop data to support long range studies into the role of alterations in expression of APPs in age-related cognitive decline. In these initial studies, we will use RT-PCR derived products and screen a degu cDNA library for APP clones. We will sequence degu APPs and amyloid precursor like proteins (APLPs). Using probes derived from the degu sequences, we will use in situ techniques to test the hypothesis that astrocytes in the aged brain over-express APP. Finally, we will look at brain region-specific APP expression in aged and young animals that were previously tested in memory and learning tasks. These pilot studies are the first to use the long-lived, amyloid forming degu to investigate questions about the role of APP in age-related cognitive decline.
