Abstract
Mutations within the β–amyloid precursor protein gene cosegregate with the early–onset form of familial Alzheimer's Disease (FAD). It is not known how these mutations result in disease; however, one early–onset AD mutation in a Swedish kindred increases potentially amyloidogenic fragments and β–protein production in cells expressing the mutant β–APP. Using a novel recombinant reporter system we found a qualitative change in the secreted product, from cleavage within the β–protein sequence to cleavage near the N–terminal region of the β–protein, even though the total amount of secreted mutant product is similar to wild–type. The results suggest that the increased formation of potentially amyloidogenic fragments in cells expressing the Swedish FAD occurs by enzymatic cleavage in the secretory pathway. Alterations in the secretory process may predispose an individual to AD.
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References
Levy, E. et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).
St. George-Hyslop, P.H. et al. The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235, 885–890 (1987).
Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein with familial Alzheimer's disease. Nature 349, 704–706 (1991).
Hardy, J. et al. Molecular classification of Alzheimer's disease. Lancet 337, 1342–1343 (1991).
Naruse, S. et al. Mis-sense mutation Val → lle in exon 17 of amyloid precursor protein in Japanese familial Alzheimer's disease. Lancet 337, 978–979 (1991).
Van Duijn, C.M. et al. Amyloid precursor protein gene mutation in early-onset Alzheimer's disease. Lancet 337, 978 (1991).
Murrell, J., Farlow, M., Ghetti, B. & Benson, M.D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254, 97–99 (1991).
Chartier-Harlin, M.-C. et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846 (1991).
Mullan, M. et al. A pathogenic mutation for probable Alzheimer's disease in the APR gene at the N-terminus of β-amyloid. Nature Genet. 1, 345–347 (1992).
Felsenstein, K. & Lewis-Higgin, L. Processing of the β-amyloid precursor protein carrying the familial, Dutch-type, and a novel recombinant C-terminal mutation. Neurosci. Lett. 152, 185–189 (1993).
Citron, M. et al. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increase β-protein production. Nature 360, 672–674 (1992).
Cai, X-D., Golde, T.E. & Younkin, S.G. Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science 259, 514–516 (1993).
Sisodia, S., Koo, E.H., Beyreuther, K., Unterbeck, A. & Price, D.L. Evidence that β-amyloid protein in Alzheimer's disease is not derived by normal processing. Science 248, 492–495 (1990).
Esch, F.S. et al. Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248, 1122–1124 (1990).
Anderson, J.P. et al. Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci. Lett. 128, 126–128 (1991).
Seubert, P. et al. Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature 361, 260–263 (1993).
Weidemann, A. et al. Identification, biogenesis and localization of precursors of Alzheimer's disease A4 amyloid protein. J. biol. Chem. 266, 16960–16964 (1989).
Sisodia, S.S. Amyloid precursor protein cleavage by a membrane bound protease. Proc. natn. Acad. Sci. U.S.A. 89, 6075–6079 (1992).
Anderson, J.P. et al. Differential brain expression of the Alzheimer amyloid precursor protein. EMBO J. 8, 3627–3632 (1989).
Anderson, J.P., Chen, Y., Kim, K.S. & Robakis, N.K. An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence. Neurochem. J. 59, 2328–2331 (1992).
Golde, T.E., Estus, S., Younkin, L., Selkoe, D.J. & Younkin, S.G. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, 728–730 (1992).
Sahasrabudhe, S.R. et al. Release of amino-terminal fragments from amyloid precursor protein reporter and mutated derivatives in cultured cells. J. biol. Chem. 267, 25602–25608 (1992).
Haass, C. et al. Targeting of cell surface β amyloid precursor to lysosomes: Alternative processing in amyloid bearing fragments. Nature 357, 500–503 (1992).
Dorner, A.J. & Kaufman, R.J. Analysis of synthesis, processing, and secretion of proteins expressed in mammalian cells. Meth. Enzymol. 185, 577–596 (1990).
Glenner, G.G. & Wong, C.W. Alzheimer's disease and Down's Syndrome: Sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131–1135 (1984).
Masters, C.L. et al. Neuronal origin of a cerebral amyloid: Neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 4, 2757–2763 (1985).
Glenner, G.G. & Wong, C.W. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 855–890 (1984).
Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell surface receptor. Nature 325, 733–736 (1987).
Busciglio, J., Gabzuda, D.H., Matsudaira, P. & Yankner, B.A. Generation of β-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc. natn. Acad. Sci. U.S.A. 90, 2092–2096 (1993).
Haass, C., Hung, A.Y., Schlossmacher, M.G., Teplow, D.B. & Selkoe, D.J. β-amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J. biol. Chem. 268, 3021–3024 (1993).
Berger, J. et al. Secreted placental alkaline phosphatase: a powerful new quantitative indicator of gene expression in eukaryotic cells. Gene 66, 1–10 (1988).
Henthorn, P. et al. Expression of a human placental alkaline phosphatase gene in transfected cells: Use as a reporter for studies of gene expression. Proc. natn. Acad. Sci. U.S.A. 85, 6342–6346 (1988).
Sayers, J.R., Schmidt, W. & Eckstein, F. 5′-3′ exonuclease in phosphorothioate-based olignucleotide directed mutagenesis. Nucl. Acids Res. 16, 791–802 (1988).
Clemmons, D.J. et al. Evaluation of a subcutaneously implanted chamber for anitbody production in rabbits. Lab. An. Sci. 4, 307–311 (1992).
Kim, K.S. et al. Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid. Neurosci. Res. Commun. 2, 121–130 (1988).
Shoji, M. et al. Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258, 126–129 (1992).
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Felsenstein, K., Hunihan, L. & Roberts, S. Altered cleavage and secretion of a recombinant β–APP bearing the Swedish familial Alzheimer's disease mutation. Nat Genet 6, 251–256 (1994). https://doi.org/10.1038/ng0394-251
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DOI: https://doi.org/10.1038/ng0394-251
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