The Alzheimer amyloid precursor protein (APP) undergoes complex processing resulting in the production of a 4-kDa amyloid peptide (A) which has been implicated in the pathogenesis of Alzheimer's disease. Recent studies have shown that cells can secrete carboxyl terminus truncated APP derivatives (APP-S) in response to physiological stimulus. We have used human central nervous system neurons (NT2N) derived from a teratocarcinoma cell line (NT2) to study the signal transduction pathways involved in APP-S secretion and A production. Muscarinic receptors (m2 and m3) as well as the heterotrimeric GTP-binding protein G and the 1 isoform of phospholipase C were present in NT2N neurons. Stimulation of the muscarinic receptor with carbachol resulted in phospholipase C activation as shown by a transient increase in the second messengers 1,2-diacyl-sn-glycerol and inositol 1,4,5-trisphosphate. Carbachol also caused an increase in intracellular Ca levels measured in single NT2N neurons. Under these conditions, carbachol caused a time-dependent 2-fold increase in APP-S secretion into the medium. In contrast, prolonged treatment with carbachol caused a decrease in A production into the medium. These results suggest that APP-S secretion and A production in NT2N neurons are regulated by the muscarinic/phospholipase C signal transduction pathway. Furthermore, activation of this pathway results in dissociation of APP-S secretion and A production.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				A. Grupe, R. Abraham, Y. Li, C. Rowland, P. Hollingworth, A. Morgan, L. Jehu, R. Segurado, D. Stone, E. Schadt, et al. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants Hum. Mol. Genet., April 15, 2007; 16(8): 865 - 873. [Abstract] [Full Text] [PDF]

				H.-W. Klafki, M. Staufenbiel, J. Kornhuber, and J. Wiltfang Therapeutic approaches to Alzheimer's disease Brain, November 1, 2006; 129(11): 2840 - 2855. [Abstract] [Full Text] [PDF]

				J. M. Camden, A. M. Schrader, R. E. Camden, F. A. Gonzalez, L. Erb, C. I. Seye, and G. A. Weisman P2Y2 Nucleotide Receptors Enhance {alpha}-Secretase-dependent Amyloid Precursor Protein Processing J. Biol. Chem., May 13, 2005; 280(19): 18696 - 18702. [Abstract] [Full Text] [PDF]

				J. L. Cummings Searching for Methods to Detect, Prevent, and Treat Alzheimer's Disease Am J Psychiatry, April 1, 2005; 162(4): 645 - 647. [Full Text] [PDF]

				M. Hashimoto, H. Kazui, K. Matsumoto, Y. Nakano, M. Yasuda, and E. Mori Does Donepezil Treatment Slow the Progression of Hippocampal Atrophy in Patients With Alzheimer's Disease? Am J Psychiatry, April 1, 2005; 162(4): 676 - 682. [Abstract] [Full Text] [PDF]

				W. Chen, J. Sulcove, I. Frank, S. Jaffer, H. Ozdener, and D. L. Kolson Development of a Human Neuronal Cell Model for Human Immunodeficiency Virus (HIV)-Infected Macrophage-Induced Neurotoxicity: Apoptosis Induced by HIV Type 1 Primary Isolates and Evidence for Involvement of the Bcl-2/Bcl-xL-Sensitive Intrinsic Apoptosis Pathway J. Virol., August 12, 2002; 76(18): 9407 - 9419. [Abstract] [Full Text] [PDF]

				W. P. Esler and M. S. Wolfe A Portrait of Alzheimer Secretases--New Features and Familiar Faces Science, August 24, 2001; 293(5534): 1449 - 1454. [Abstract] [Full Text] [PDF]

				B. Borroni, F. Colciaghi, L. Pastorino, C. Pettenati, E. Cottini, L. Rozzini, R. Monastero, G. L. Lenzi, F. Cattabeni, M. Di Luca, et al. Amyloid Precursor Protein in Platelets of Patients With Alzheimer Disease: Effect of Acetylcholinesterase Inhibitor Treatment Arch Neurol, March 1, 2001; 58(3): 442 - 446. [Abstract] [Full Text] [PDF]

				T. R. Neelands, A. P. J. King, and R. L. Macdonald Functional Expression of L-, N-, P/Q-, and R-Type Calcium Channels in the Human NT2-N Cell Line J Neurophysiol, December 1, 2000; 84(6): 2933 - 2944. [Abstract] [Full Text] [PDF]

				D. M. Skovronsky, D. B. Moore, M. E. Milla, R. W. Doms, and V. M.-Y. Lee Protein Kinase C-dependent alpha -Secretase Competes with beta -Secretase for Cleavage of Amyloid-beta Precursor Protein in the Trans-Golgi Network J. Biol. Chem., January 28, 2000; 275(4): 2568 - 2575. [Abstract] [Full Text] [PDF]

				G. S. Kelner, M. Lee, M. E. Clark, D. Maciejewski, D. McGrath, S. Rabizadeh, T. Lyons, D. Bredesen, P. Jenner, and R. A. Maki The Copper Transport Protein Atox1 Promotes Neuronal Survival J. Biol. Chem., January 7, 2000; 275(1): 580 - 584. [Abstract] [Full Text] [PDF]

				D. S. Howland, S. P. Trusko, M. J. Savage, A. G. Reaume, D. M. Lang, J. D. Hirsch, N. Maeda, R. Siman, B. D. Greenberg, R. W. Scott, et al. Modulation of Secreted beta -Amyloid Precursor Protein and Amyloid beta -Peptide in Brain by Cholesterol J. Biol. Chem., June 26, 1998; 273(26): 16576 - 16582. [Abstract] [Full Text] [PDF]

				C. Jolly-Tornetta, Z.-y. Gao, V. M.-Y. Lee, and B. A. Wolf Regulation of Amyloid Precursor Protein Secretion by Glutamate Receptors in Human Ntera 2 Neurons (NT2N) J. Biol. Chem., May 29, 1998; 273(22): 14015 - 14021. [Abstract] [Full Text] [PDF]

				A. C. LeBlanc, M. Koutroumanis, and C. G. Goodyer Protein Kinase C Activation Increases Release of Secreted Amyloid Precursor Protein without Decreasing Abeta Production in Human Primary Neuron Cultures. J. Neurosci., April 15, 1998; 18(8): 2907 - 2913. [Abstract] [Full Text] [PDF]

				Y.-L. Guo, K. Baysal, B. Kang, L.-J. Yang, and J. R. Williamson Correlation between Sustained c-Jun N-terminal Protein Kinase Activation and Apoptosis Induced by Tumor Necrosis Factor-alpha in Rat Mesangial Cells J. Biol. Chem., February 13, 1998; 273(7): 4027 - 4034. [Abstract] [Full Text] [PDF]

				J. Mills, D. Laurent Charest, F. Lam, K. Beyreuther, N. Ida, S. L. Pelech, and P. B. Reiner Regulation of Amyloid Precursor Protein Catabolism Involves the Mitogen-Activated Protein Kinase Signal Transduction Pathway J. Neurosci., December 15, 1997; 17(24): 9415 - 9422. [Abstract] [Full Text] [PDF]

				I. H. Ulus and R. J. Wurtman Metabotropic Glutamate Receptor Agonists Increase Release of Soluble Amyloid Precursor Protein Derivatives from Rat Brain Cortical and Hippocampal Slices J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 149 - 154. [Abstract] [Full Text]

				R. S. Turner, N. Suzuki, A. S. C. Chyung, S. G. Younkin, and V. M.-Y. Lee Amyloids beta[IMAGE] and beta[IMAGE] Are Generated Intracellularly in Cultured Human Neurons and Their Secretion Increases with Maturation J. Biol. Chem., April 12, 1996; 271(15): 8966 - 8970. [Abstract] [Full Text] [PDF]

				R. M. Nitsch, M. Deng, J. H. Growdon, and R. J. Wurtman Serotonin 5-HT2a and 5-HT2c Receptors Stimulate Amyloid Precursor Protein Ectodomain Secretion J. Biol. Chem., February 23, 1996; 271(8): 4188 - 4194. [Abstract] [Full Text] [PDF]