Phosphoproteins and Alzheimer's disease
Paul Greengard, PhD Rockefeller University
We will characterize protein phosphorylation, the major mechanism through which extracellular stimuli regulate intracellular functions, in specific brain regions related to Alzheimer's disease. These regions include the basal nucleus of Meynert and related basal forebrain regions, and the hippocampus and related cortical regions. We will analyze the distribution of both cyclic AMP- and cyclic GMP-regulated, Ca2+ /calmodulin-regulated, and Ca2+/phospholipid-regulated protein phosphorylation systems in these regions. We will study the regional, cellular and subcellular localization of individual phosphoproteins in these regions. Phosphoproteins specifically related to these brain regions will then be further analyzed by biochemical, physiological and pharmacological methods, to identify both factors which regulate the content of the proteins and their state of phosphorylation, and to suggest possible functional roles of the proteins. Quantitative biochemical and immunological assays will be developed for use in possible studies on clinical and pathological material. Antibodies will be developed possible immunocytochemical localization studies. Pharmacological studies will try to identify possible therapeutic targets related to cholinergic neurotransmission and other deficits known to exist in Alzheimer's disease. The results of such combined studies are expected to improve our understanding of both the morphological organization and the biochemical, physiological and pharmacological properties of these brain regions. Furthermore, use of these results in the study of Alzheimer's disease would be expected to improve both diagnosis, prognosis and therapy.