Linda A. Dokas, Ph.D.: Laboratory Research Program
My laboratory uses biochemical techniques to investigate intracellular signaling mechanisms and their role in the pathogenesis of Alzheimer's Disease. Less is known regarding the factors that regulate the normal metabolism of the neuronal amyloid precursor protein (APP) than of its aberrant processing to the b-amyloid peptide (Ab) in relation to the pathology of Alzheimer's disease. However, accumulation of information on the former would not only be of interest for the study of the basic regulatory mechanisms that govern APP function, but could also be of therapeutic value since the normal and aberrant pathways through which the APP is processed are inter-related. Therefore, my laboratory is interested in the characterization of biochemical mechanisms that regulate APP secretion, with an emphasis on the presynaptic pool of the APP. Two general questions are being considered: 1.) What is the functional significance of presynaptic APP secretion? 2.) What specific aspects of neurotransmitter receptor-mediated APP secretion can be identified as potential therapeutic targets?
A second major research interest is on the regulation of protein expression in the brain by glucocorticoid hormones in relation to two significant findings from my laboratory. Previously, we have found that elevation of plasma glucocorticoid levels in the rat, whether by administration of exogenous steroid or ACTH or by stress, will increase the synthesis of an oligodendrocytic protein, glycerol phosphate dehydrogenase (GPDH), in thehippocampus. Current efforts are directed toward analysis of the functional significance of this steroid-mediated effect. We are examining the possibility that GPDH induction is an adaptation to hyper-osmotic stress and that the induction is mediated by a mitogen-activated protein kinase (MAPK) pathway as it is in other experimental systems. Secondly, we have found that glucocorticoid-mediated effects on protein expression are specific for the conditions under which proteins are synthesized. For example, when brain slices are prepared from control and steroid-treated rats and incubated under physiological conditions, the most prominent steroid-mediated effect is the increased synthesis of GPDH. However, slices incubated under heat shock conditions demonstrate a different pattern of protein synthesis and , in response to steroid treatment, decreased synthesis of two unidentified hippocampal proteins and increased synthesis of the small heat shock protein, HSP27, in the cerebellum. Slices incubated under ischemic conditions show yet a third pattern of overall and steroid-determined protein synthesis. Thus, it appears that cellular insults elicit specific responses in the form of patterns of protein synthesis in the brain. One goal of my research is to understand the functional significance of the ability of glucocorticoid hormones to modulate these stimulus-specific patterns of protein synthesis. Julie Niswander is a Ph.D. student in the Cellular and Molecular Neurobiology program in my laboratory. She has a B.S. in Zoology from Miami University (1997). Her current research project concerns the regulation of MAPK pathways in the brain in relation to stress and aging.