This application requests continued support for research on two families of chemicals in brain membranes - the phosphatides (e.g., phosphatidylcholine; PC) and amyloid-precursor protein (APP) - which may be involved in causing Alzheimer's disease (AD). Research conducted in our laboratory since this program's last competitive review (June, 1992) has shown, among other things, that the production of APP - like, as we previously showed, its conversion to non-amyloidogenic (i.e. presumably non-toxic) soluble forms - can be controlled by brain neurotransmitters (norepinephrine acting via beta receptors) and second messengers (cyclic AMP); that levels of cytidine in brain and in individual cells can limit the production of PC's immediate precursor, CDP-choline; that-as a consequence - CDP-choline can be used as a drug to treat strokes and memory impairment; and that when some cells are called upon to increase the rate at which they produce new membranes (e.g., neurite outgrowth in PC12 cells exposed to Nerve Growth Factor), the limiting factor in this process is a """"""""second messenger"""""""", diacylglycerol (DAG) which in this circumstance acts as a bulk constituent. (The ability of orally- administered CDP-choline to diminish stroke-induced neurological deficits has been demonstrated elsewhere in two large-scale """"""""Phase III"""""""" studies, and a Now Drug Application [NDA] relating to this use will undergo evaluation by the FDA.) The new studies that we propose continue these lines of research, and relate to the synthesis, metabolism, and possible functions of APP; the sources of cytidine to the brain, and its interactions with choline and phospholipids; and the sources of the DAG needed to sustain neurite outgrowth. As before, we will attempt to apply our findings to the treatment of human diseases whenever possible.
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