This program project grant is focused on understanding the 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. The first theme is to examine the role of oxidative stress in aging. Projects 13, 15, 4 and 16 will continue their collaboration regarding nutritional interventions with diets high in antioxidants. Thus we will extend our studies of interventions with antioxidants to LTP and also possible synergy with neurotrophins. A new theme for the renewal that threads through our program is the investigation of inflammatory processes in aging and its relation to oxidative stress. Project 13 and Project 4 have examined a line of rats resistant to oxidative stress that has an increased life span and does not show age-related declines in cerebellar physiology and motor learning, or age-related atrophy of basal forebrain cholinergic neurons. These rats have a deficiency in a microglial cell adhesion molecule (LFA-l), indicating reduced inflammation in aging, and a reduction in reactive oxygen species (ROS). The role of inflammation will be studied from a therapeutic angle in Project 14 looking at NSAIDS and specific COX-2 inhibitors. A third theme is related to biological substrates of age-related changes in cellular models for learning and memory, such as long-term potentiation (LTP). Projects 15 and 4 will examine trophic factor interactions with LTP, using intraocular transplants of hippocampus at different ages and denervation and NGF treatment as paradigms for NGF release. Project 3 will investigate PKA-dependent synthesis of AMPA receptors, and the transcriptional regulation of AMPA receptors by trophic factors will be examined in Project 16. Project 13 will examine alterations in PKA with age that will relate to these projects as well. Another focus of our program is age-related alterations of the basal forebrain cholinergic system; nicotinic receptors are studied in Project 14 and neurotrophic support in Project 4. Our particular strength is the multidisciplinary approach in our different research groups, from the whole animal behavior to single cell recording, morphology, and biochemical assays of protein levels. The long-term goal of our program is to understand the basic biological mechanisms of aging and cognition that will lead to new therapies for Alzheimer's disease and other age-related cognitive diseases.
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