Generation and regulation of beta-amyloid peptide variants by neurons

Gouras, G.K., Xu, H.X., Jovanovic, J.N., Buxbaum, J.D., Wang, R., Greengard, P., Relkin, N.R. and Gandy, S. (1998) Generation and regulation of beta-amyloid peptide variants by neurons. Journal of Neurochemistry, 71 (5). pp. 1920-1925. 10.1046/j.1471-4159.1998.71051920.x.

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DOI: 10.1046/j.1471-4159.1998.71051920.x

Abstract

Studies of processing of the Alzheimer beta-amyloid precursor protein (PAPP) have been performed to dale mostly in continuous cell lines and indicate the existence of two principal metabolic pathways: the "beta-secretase" pathway, which generates beta-amyloid (A beta(1-40/42); similar to 4 kDa), and the "alpha-secretase" pathway, which generates a smaller fragment, the "p3" peptide (A beta(17-40/42); similar to 3 kDa), To determine whether similar processing events underlie PAPP metabolism in neurons, media were examined following conditioning by primary neuronal cultures derived from embryonic day 17 rats. Immunoprecipitates of conditioned media derived from [S-35]methionine pulse-labeled primary neuronal cultures contained 4- and 3-kDa A beta-related species. Radiosequencing analysis revealed that the 4-kDa band corresponded to conventional A beta beginning at position A beta(Asp(1)), whereas both radiosequencing and immunoprecipitation-mass spectrometry analyses indicated that the 3-kDa species in these conditioned media began with A beta(Glu(11)) at the N terminus, rather than A beta(Leu(17)) as does the conventional p3 peptide. Either activation of protein kinase C or inhibition of protein phosphatase 1/2A increased soluble PAPP, release and decreased generation of both the 4-kDa A beta and the 3-kDa N-truncated A beta. Unlike results obtained with continuously cultured cells, protein phosphatase 1/2A inhibitors were more potent at reducing A beta secretion by neurons than were protein kinase C activators. These data indicate that rodent neurons generate abundant A beta variant peptides and emphasize the role of protein phosphatases in modulating neuronal A beta generation.

Item Type:Article
Uncontrolled Keywords:Alzheimer's disease; beta-amyloid peptides; amyloid precursor protein; neurons; protein kinase; protein phosphatase
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:2028
Journal or Publication Title:Journal of Neurochemistry
Deposited By:Library Staff
Deposited On:07 Apr 2011 12:52
Last Modified:07 Apr 2011 12:52

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