Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose cause is unknown and for which an effective therapy dose not exist. The present application proposes 5 years the funding of the University of Florida Drug Discovery Group for Alzheimer's Disease (UF-DDG) to continue the process of hypothesis-driven research into the mechanism(s), models and discovery of efficacious therapies that affect the underlying neuropathologies of AD. Four research projects and 4 supportive cores will continue the discovery of drug in 4 different therapeutic classes with efficacy in protecting neuron in vivo and in vitro and in enhancing memory- related behaviors in learning/memory deficient animal models. For a drug to emerge from our preclinical assessment and enter animal toxicity assessments, it must show neuroprotective and memory-enhancing activity. During the first funding period, this process has resulted in 3 drugs in 2 therapeutic classes entering clinical trial for efficacy assessment in AD. The present program of research proposes the assessment of the mechanism of action of the neuroprotective and cognitive-enhancing effects of our compounds, and the synthesis of novel compounds that are indicated from our studies. In Project 1, James W. Simpkins we will assess the neuroprotective activities of the estratrienes, a group of estrogen-like compounds that we have shown to be neuroprotective in a variety of in vitro and in vivo models and cognitive-enhancing in animals. Project 2, Edwin Meyer will determine the neuroprotective mechanism of novel alpha7 nicotinic agonists and we will synthesis new agonist, based upon discovered structure-activity relationships. In Project 3, Jeffrey Hughes/Edwin Meyer will continue their work on non-viral methods for the delivery of a nerve growth factor gene into brain neurons, using novels cationic liposomes that incorporate pH sensitive surfactants, designed to increase the transfection rate of the gene. The 4 cores are i) Administration, ii) Tissues Culture, iii) Animal Care and Behavioral Assessment, and iv) Neurochemistry. Collectively, these core will provide organization, reagents and services that are vital to the success of the program. In summary, this program of research will continue to discover novel drugs (and drug mechanisms) that are of potential efficacy in the treatment of the neurodegeneration and cognitive decline associated with AD.