Phosphoproteins and Alzheimer's disease

Paul Greengard, PhD
Rockefeller University (New York, NY)
Year Awarded:
1986
Grant Duration:
April 1, 1986 to March 31, 1987
Disease:
Alzheimer's Disease
Award Amount:
$48,000
Grant Reference ID:
A1986022
Award Type:
Standard
Award Region:
US Northeastern
Paul Greengard, PhD

Phosphoproteins and Alzheimer's disease

Details


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.

Publications

Foster, G. A., Schultzberg, M., Hijkfelt, T., et al. (1987) Development of a dopamine- and cyclic adenosine 3':5'monophosphate-regulated phosphoprotein (DARPP-32) in the prenatal rat central nervous system, and its relationship to the arrival of presumptive dopaminergic innervation. J. Neurosci. 7:1994-2018.  

[Book Chapter] Hemmings, H.C. Jr., Walaas, S.I., Ouimet, C.C., and Greengard, P. (1987) Dopamine receptors: regulation of protein phosphorylation. In: Receptor Biochemistry and Methodology, Volume 9, Structure and Function of Dopamine Receptors, I. Creese and C. M. Fraser, eds., Alan R. Liss, Inc., New York, pp. 115-151.

[Book Chapter] Hemmings, H.C. Jr., Nestler, E.J., Walaas, S.I., Ouimet, C.C., and Greengard, P. (1987) Protein phosphorylation and neuronal function: DARPP-32, an illustrative example. In: Synaptic Function, G M. Edelman, W.E. Gall, and W.M. Cowan, eds., John Wiley and Sons, New York, pp. 213-240.

[Book Chapter] Walaas, S.I., Ouimet, C.C., Hemmings, H.C. Jr., and Greengard, P. (1986) DARPP-32: A dopamine-regulated phosphoprotein in the basal ganglia. In: Dopaminergic Systems and their Regulation, G.N. Woodruff, J.A. Post, and P.J. Roberts, eds., Macmillan Press, pp. 165-179.

[Book Chapter] Walaas, S.I., Wang, J.K.T., and Greengard, P. (1986) First messengers, second messengers, and protein phosphorylation in CNS. In: Fast and Slow Chemical Signalling in the Nervous System, L.L. Iversen, and E. Goodman, eds. Oxford University Press, New York, pp. 151-163.

Everitt, B.J., Meister, B., Hijkfelt, T., et al. (1986) The Hypothalamic arcuate nucleus-median eminence complex: Immunohistochemistry of transmitters, peptides and DARPP-32 with special reference to coexistence in dopamine neurons. Brain Res. Rev. 11:97-155.  

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