This program is designed to bring together investigators representing widely diverse scientific backgrounds for the purpose of investigating the mechanisms of action of drugs of potential use in treatment of Alzheimer Disease (AD). The goals include studies of mechanisms of action of AD drugs currently under evaluation and development of model systems for evaluation of AD drugs which may be available in the future. This program will formalize already existing collaborations among several of the investigators. The initial focus will be the study of the effects of acetyl-L-carnitine (ALC) and nerve growth factor (NGF). Project 1 will study specific electron transport chain defects and free radical mechanisms in AD and ways in which ALC ameliorates these effects. This project will make use of animal models of AD and of a recently devised human fibroblast system for studying drug effects. This project will interface tightly with project 2. Project 2 will continue ongoing studies of the physical chemistry of the ALC molecule at the biochemical level. Preliminary studies indicate that ALC is a potent iron chelator. This finding suggests that ALC may serve to suppress hydroxy radical formation by reducing the availability of iron needed for catalysis (Fenton reaction). This project will work in coordination with project 1 by using electron paragmagnetic resonance based spin trap methods to quantitate free radical production in the model systems worked out in project molecule which can then be evaluated by projects 1 and 3. Project 3 will use a molecular biology approach to study the mode of action of NGF at a cellular level. The effects of NGF on mitochondrial biogenesis and metabolism will be evaluated. Expression of the APP gene will be evaluated using a model fibroblast culture system devised in project 1. This program will uncover data concerning the mode of action of two promising AD drugs, will provide model systems of evaluation of new AD drugs, provide data needed for design of new drugs, and bring together a group of investigators capable of approaching the AD therapy problem from widely diverse points of view.
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