Summary
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1.
Amyloid plaques found in the brains of Alzheimer's diseased patients are composed of the 42 amino acid beta-amyloid peptide (BAP) which is processed out of the larger amyloid precursor protein (APP).
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2.
To study the regulation of the APP gene expression, we have isolated the promoter region of this angle of this single-copy gene and produced a reporter gene system to determine if the promoter is responsive to agents that may cause the overproduction of APP leading to the abnormal accumulation of plaques in AD.
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3.
The promoter contains sequences homologous to heat shock elements, AP-1 binding sites, and phorbol ester-inducible sequences as well as GG-rich regions found in other constitutively expressed genes.
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4.
We show here that this promoter is inducible in cultured cells by interleukin-1 (IL-1) in a transient assay system and that the HSE and AP-1 binding site are required for this inducibility.
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5.
This induction of transcription from the APP promoter implies that this gene is responsive to tropic and/or trophic agents which may be present in the diseased brain.
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References
Angel, P., Imagawa, M., Chiu, R., Stein, B., Imbra, R. J., Rahmsdorf, H. J., Jonat, C., Herrlich, P., and Karin, M. (1987). Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor.Cell 49729–739.
Bahmanyar, S., Higgins, G. A., Goldgaber, D., Lewis, D. A., Morrison, J. H., Wilson, M. C., Shankar S. K., and Gajdusek, D. C. (1987). Localization of amyloid B protein messenger RNA in brains from patients with Alzheimer's disease.Science 23777–80.
Barrera-Saldana, H., Takahashi, K., Vigneron, M., Wildeman, A., Davidson, I., and Chambon, P. (1985). All six GC-motifs of the SV40 early upstream element contribute to promoter activity in vivo and in vitro.EMBO J. 43839–3849.
Cohen, M. L., Golde, T. E., Usiak, M. F., Younkin, L. H., and Younkin S. G. (1988). In situ hybridization of nucleus basalis neurons shows increased B-amyloid mRNA in Alzheimer disease.Proc. Natl. Acad. Sci. USA 851227–1231.
Curran, T., and Franza, B. R., Jr. (1988). Fos and jun: The AP-1 connection.Cell 55395–397.
Donnelly, R. J., Rasool, C. G., Bartus, R., Vitek, S., Blume, A. J., and Vitek, M. (1988). Multiple forms of beta-amyloid peptide precursor RNAs in a single cell type.Neurobiol. Aging 9333–338.
Donnelly, R. J., Jacobsen, J. S., Rasool, C. G., Bartus, R., Blume, A. J., and Vitek, M. (1989). Isolation and expression of multiple forms of beta amyloid protein precursor cDNAs. InAlzheimer's Disease and Related Disorders (K. Iqbal, H. M. Wisniewski, and B. Winblad. Eds.), Allan R. Liss, New York.
Dyrks, T., Weidemann, A., Multhaup, G., Salbaum, J. M., Lemaire, H.-G., Kang, J., Muller-Hill, B., Masters, C. L., and Beyreuther, K. (1988). Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease.EMBO J. 4949–957.
Glenner, G. G. (1988). Alzheimer's diseases: Its proteins and genes.Cell 52307–308.
Goedert, M., Fine, A., Hunt, S. P., and Ullrich, A. (1986). Nerve growth factor mRNA in peripheral and central rat tissues and in the human nervous system: Lesion effects in the rat brain and levels in Alzheimer's disease.Mol. Brain Res. 185–92.
Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U., and Gajdusek, D. C. (1987). Characterization and chromosomal location of a cDNA encoding brain amyloid of Alzheimer's disease.Science 235877–880.
Goldgaber, D., Harris, H. W., Hla, T., Maciag, T., Donnelly, R. J., Jacobsen, J. S., Vitek, M. P., and Gajdusek, D. C. (1989). Interleukin 1 regulates synthesis of of amyloid B-protein precursor mRNA in human endothelial cells.Proc. Natl. Acad. Sci. USA 867606–7610.
Higgins, G. A., Lewis, D. A., Bahmanyar, S., Goldgaber, D., Gajdusek, D. C., Young, W. G., Morrison, J. H., and Wilson, M. C. (1988). Differential regulation of amyloid-B-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease.Proc. Natl. Acad. Sci. USA 851297–1301.
Kitagutchi, N., Takahashi, Y., Tokushima, Y., Shiojiri, S., and Ito, H. (1988). Novel precursor of Alzhiemer's disease amyloid protein shows protease inhibitor activity.Nature 331530–532.
La Fauci, G., Lahiri, D. K., Salton, S. R. J., and Robakis, N. K. (1989). Characterization of the 5′-end region and the first two exons of the B-protein precursor gene.Biochem. Biophys. Res. Comm. 159297–304.
Lemaire, H. G., Saldbaum, J. M., Multhaup, G., Kang, J., Bayney, T. M., Unterbeck, A., Beyreuther, K., and Muller-Hill, B. (1989). The preA4695 precursor protein of Alzheimer's disease A4 amyloid is encoded by 16 exons.Nucl. Acids. Res. 17517–522.
Lin, J.-X., and Vilcek, J. (1987). Tumor necrosis factor and interleukin-1 cause a rapid and transient stimulation of c-fos and c-myc mRNA levels in human fibroblasts.J. Biol. Chem. 26211908–11911.
Lindholm, D., Heumann, R., Hengerer, B., and Thoenen, H. (1988). Interleukin 1 increases stability and transcription of mRNA encoding nerve growth factor in cultured rat fibroblasts.J. Biol. Chem. 26316348–16351.
Mobley, W. C., Neve, R. L., Prusiner, S. B., and McKinley, M. P. (1988). Nerve growth factor increases mRNA levels for the prion protein and the B-amyloid protein precursor in developing hamster brain.Proc. Natl. Acad. Sci. USA 859811–9815.
Nishizuka, Y. (1984). The role of protein kinase C in cell surface signal transduction and tumour promotion.Nature 308693–698.
Palmert, M. R., Golde, T. E., Cohen, M. L., Kovacs, D. M., Tanzi, R. E., Gusellar, J. F., Usiak, M. F., Younkin, L. H., and Younkin, S. G. (1988). Amyloid protein precursor messenger RNAs: Differential expression in Alzheimer's disease.Science 2411080–1084.
Rosoff, P. M., Savage, N., and Dinarello, C. A. (1988). Interleukin-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism.Cell 5473–81.
Salbaum, J. M., Weidemann, A., Lemaire, H.-G., Masters, C. L., and Beyreuther, K. 1988. The promoter of Alzheimer's disease amyloid A4 precursor gene.EMBO. J. 72807–2813.
Sanger, F., Nicklen, S., and Coulson, A. R. (1977). DNA sequencing with chain termination inhibitors.Proc. Natl. Acad. Sci. USA 745463–5467.
Sax, C. M., Farrell, F. X., Tobian, J. A., and Zehner, Z. E. (1988). Multiple elements are required for expression of an intermediate filament gene.Nucl. Acids. Res. 168057–8076.
Sehgal, A., Patil, N., and Chao. M. (1988). A constitutive promoter directs expression of the nerve growth factor receptor gene.Mol. Cell. Biol. 83160–3167.
Selden, R. F., Howie, K. B., Rowe, M. E., Goodman, H. M., and Moore, D. D. (1986). Human growth hormone as a reporter gene in regulation studies employing transient gene expression.Mol. Cell. Biol. 63173–3179.
St. George-Hyslop, P. H., Tanzi, R. E., Polinsky, R. J.,et al. (1987). The genetic defect causing familial Alzheimer's disease maps on chromosome 21.Science 235885–890.
Tanzi, R. E., Gusella, J. F., Watkins, P. C., Bruns, G. A. P., St. George-Hyslop P., Van Keuren, M. L., Patterson, D., Pagan, S., Kurnit, D. M., and Neve, R. L. (1987). Amyloid B protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus.Science 235880–884.
Tanzi, R. E., McClatchey, A., Lampert, E., Villa-Kamarof, L., Gusella, J., and Neve, R. (1988). Protease inhibitor domain encoded by an amyloid precursor mRNA associated with Alzheimer's diseas.Nature 331525–527.
Tanzi, R. E., St. George-Hyslop, P. H., and Gusella, J. F. (1989). Molecular genetic approaches to Alzheimer's disease.Trends in Neuro Sciences 12152–158.
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Donnelly, R.J., Friedhoff, A.J., Beer, B. et al. Interleukin-1 stimulates the beta-amyloid precursor protein promoter. Cell Mol Neurobiol 10, 485–495 (1990). https://doi.org/10.1007/BF00712843
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DOI: https://doi.org/10.1007/BF00712843