Mechanisms and use of antidiabetic agents in brain aging and Alzheimer's Disease

Alzheimer's disease (AD), the third most costly disease in the United States after cardiac disease and cancer, is increasing in incidence and moving from th to 5th as one of the leading causes of death among the elderly. While current research efforts continue to address the underlying processes responsible for the progressive decline in cognitive function seen during aging, available medical treatments are still very limited. However, recent results from both clinical and preclinical studies suggest that antidiabetic agents (e.g., thiazolidinediones - TZDs) may be beneficial in retarding the devastating transition from normal brain aging to AD. A few human and animal studies have shown that use of rosiglitazone (a TZD) can improve memory and lead to cognitive improvements during aging and/ or AD. These results appear to provide compelling preliminary evidence to support the use of antidiabetic drugs to combat aging-associated cognitive impairment and AD pathology. However, little is known about the underlying molecular mechanisms, or about the identity of the CNS targets of TZDs. Some of the proposed beneficial effects of TZDs include reestablishment of insulin sensitivity and associated peripheral and/or CNS glucose utilization, along with reductions in inflammatory cytokines, Af31-42deposits, microglial activation, and intracellular Ca2+ levels. Given that Ca2+ dysregulation is considered a hallmark of brain aging and is also present in animal models of diabetes, we propose that some Ca2+ biomarkers of brain aging may be targets of TZDs. Using electrophysiological, molecular and Ca2+ imaging techniques, along with a team of qualified scientists, this project will test the overall h}'pothesis that some TZDs can improve cognitive status in aged animals, by reducing key Ca2+ biomarkers of brain aging and neurodegeneration in the hippocampus. The following Specific Aims will determine the molecular bases underlying the potential use of TZDs in preventing memory loss during aging: 1) testing the hypothesis that TZDs act in the hippocampus to normalize Ca2+ levels within neurons and/or glial cells; and 2) testing the prediction that in vivo TZD treatment can improve cognition in aged animals in parallel with restoring Ca2+ homeostasis. Results from the proposed studies may provide a rationale and a mechanistic basis for the therapeutic application of TZDs in preventing/ retarding the cognitive decline seen during aging. Furthermore, these studies may contribute to future drug development of similar or new TZDderived compounds for the treatment of AD.