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Modulation of APP Processing by Neurotransmission

  • Roger M. Nitsch
  • Barbara E. Slack
  • Steven A. Farber
  • Meihua Deng
  • Paul R. Borghesani
  • Richard J. Wurtman
  • John H. Growdon
Part of the Advances in Behavioral Biology book series (ABBI, volume 44)

Abstract

Brain amyloid deposits are invariant neuropathological hallmarks of Alzheimer’s disease (AD) and Down’s syndrome, and are sometimes also found in lesser amounts in brains of neuropsychologically normal, aged human subjects. AD-type brain amyloid consists of aggregated Aß peptides which are 39–43 amino acid residues in length. Aß is derived, by proteolytic processing, from a larger amyloid ß-protein precursor (APP), which is a transmembrane glycoprotein that contains a single membrane spanning domain, a large N-terminal ectodomain and a short cytoplasmic C-terminal tail. The Aß domain is located within the ectodomain and extends with its hydrophobic C-terminal region 11-15 residues into the membrane. APP exists in various forms generated by alternative splicing of mRNA derived from a single gene on chromosome 21 (for review, see Kosik, 1992). APP is highly conserved and expressed at high levels in brain and, at lower levels, in many peripheral tissues. The biological function of APP is unclear but accumulating evidence suggests roles in cell adhesion (Schubert et al., 1989), in neurite outgrowth (Milward et al., 1992), as well as excitoprotective functions via the regulation of intracellular calcium concentrations (Mattson et al., 1993). Mature APP is rapidly degraded by various alternative proteolytic processing pathways. Proteolytic derivatives are secreted into the extracellular space and are found at high concentrations in human cerebrospinal fluid. Secreted APP derivatives include the large N-terminal ectodomain, termed APPs (Esch et al., 1990; Sisodia et al., 1990) and ~4KDa Aß-peptides (Haass et al., 1992; Shoji et al., 1992) that potentially can aggregate into amyloid. In addition to the secretory processing pathways, full-length APP can be internalized from the cell surface and targeted to the endosomal-lysosomal system (Haass et al., 1992), where multiple cleavage products are generated. Some of these contain the intact ßA4 domain and thus are also potentially amyloidogenic (Golde et al., 1992; Estus et al., 1992). Aß is neurotoxic in some experimental systems (Yankner et al., 1990) and may induce apoptosis (Loo et al., 1993). Thus, APP processing pathways yielding either Aß or APPs are likely to have distinct cellular consequences: processing events that generate Aß may be toxic and are potentially amyloidogenic, whereas APP processing to yield APPs generate trophic and precludes APP’s role as an amyloidogenic molecule. It thus becomes important to understand the cellular mechanisms involved in the regulation of APP processing pathways.

Keywords

Phorbol Ester Human Cerebrospinal Fluid Chelerythrine Chloride APpS Secretion Aged Human Subject 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkas-Kramarski, R., Jaffe, E,A„ Gandy, S.E., and Greengard, P. 1992, Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer ß/A4 amyloid protein precursor. Proc. Natl. Acad. Sci. USA 89: 10075–10078.PubMedCrossRefGoogle Scholar
  2. Cai, X-D., Golde, T.E., and Younkin, S.G., 1993, Release of excess amyloid ß-protein from a mutant amyloid ß-protein precursor, Science 259: 514–516.PubMedCrossRefGoogle Scholar
  3. Caporaso, G.L., Gandy, S.E., Buxbaum, J.D., Ramabhadran, T.V., and Greengard, P., 1992, Protein phosphorylation regulates secretion of Alzheimer ß/A4 amyloid precursor protein. Proc. Natl. Acad. Sci. USA 89: 3055–3059.PubMedCrossRefGoogle Scholar
  4. Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A.Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., and Selkoe, D.J., 1992, Mutation of the ß-amyloid precursor protein in familial Alzheimer’s disPAsP increases b-protein production, Nature 360: 672–674.PubMedCrossRefGoogle Scholar
  5. Esch, F.S., Keim, P.S., Beattie, E.C., Blacher, R.W., Culwell, A.R., Oltersdorf, T., McClure, D., and Ward, P., 1990, Cleavage of amyloid ß-peptide during constitutive processing of its precursor, Science 248: 1122–1124.PubMedCrossRefGoogle Scholar
  6. Estus, S., Golde, T.E., Kunishita, T., Blades, D., Lowery, D., Eisen, M., Usiak, M., Qu, X., Tabira, T., Greenberg, B.D., and Younkin, S.G., 1992, Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor, Science 255: 726–728.PubMedCrossRefGoogle Scholar
  7. Golde, T.E., Estus, S., Younkin, L.H., Selkoe, D.J., and Younkin, S. G., 1992, Processing of the amyloid protein precursor to potentially amyloidogenic derivatives, Science 255: 728–730.PubMedCrossRefGoogle Scholar
  8. Haass, C., Koo, E.H., Mellon, A., Hung, A.Y., and Selkoe, D.J., 1992, Targeting of cell-surface 0- amyloid precursor protein to lysosomes: Alternative processing into amyloid-bearing fragments, Nature 357: 500–503.PubMedCrossRefGoogle Scholar
  9. Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B.L., Lieberburg, I., Koo, E.H., Schenk, D., Teplow, D.B., and Selkoe, D.J., 1992, Amyloid ß-peptide is produced by cultured cells during normal metabolism, Nature 359: 322–325.PubMedCrossRefGoogle Scholar
  10. Hung, A.Y., Haass, C., Nitsch, R.M., Qiu, W.Q., Citron, M., Wurtman, R.J., Growdon, J.H., and Selkoe, D.J., 1993, Activation of protein kinase C inhibits cellular production of the amyloid ß-protein. J. Biol. Chem. 268: 22959–22962PubMedGoogle Scholar
  11. Hung, A.Y., and Selkoe, D.J., 1994, Selective ectodomain phosphorylation and regulated cleavage of ß amyloid precursor protein. EMBO J.,in press.Google Scholar
  12. Kosik, K.S., 1992, Alzheimer’s disease: A cell biological perspective, Science 256: 780–783.PubMedCrossRefGoogle Scholar
  13. Loo, D.T., Copani, A., Pike, C.J., Whittemore, E.R., Walencewicz, A.J., Cotman, C.W., 1993, Apoptosis is induced by ß-amyloid in cultured central nervous system neurons, Proc. Natl. Acad. Sci. USA 90: 7951–7955.PubMedCrossRefGoogle Scholar
  14. Mattson, M.P., Cheng, B., Culwell, A.R., Esch, F.S., Lieberburg, I., Rydel, R.E., 1993, Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the ß-amyloid precursor protein, Neuron 10: 243–254.PubMedCrossRefGoogle Scholar
  15. Milward, E.A., Papadopoulos, R., Fuller, S.J., Moir, R.D., Small, D., Beyreuther, K., and Masters, C.L., 1992, The amyloid protein precursor of Alzheimer’s disease is a mediator of the effects of nerve growth factor on neurite outgrowth, Neuron 9: 129–137.PubMedCrossRefGoogle Scholar
  16. Nitsch, R.M., Farber, S.A., Growdon, J.H., and Wurtman, R.J., 1993 Release of amyloid fl-protein precursor derivatives by electrical depolarization of rat hippocampal slices, Proc. Natl. Acad. Sci. USA 90: 5191–5193.PubMedCrossRefGoogle Scholar
  17. Nitsch, R.M., and Growdon, J.H., 1994, The role of neurotransmission in the regulation of amyloid ß-protein precursor processing, Biochem. Pharmacol. in press.Google Scholar
  18. Nitsch, R.M., Slack, B.E., Wurtman, R.J., and Growdon, J.H., 1992, Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors, Science 258: 304307.Google Scholar
  19. Schubert, D., En, L-W, Saitoh, T., and Cole, G., 1989, The regulation of amyloid ß-precursor secretion and its modulatory role in cell adhesion, Neuron 3: 689–694.PubMedCrossRefGoogle Scholar
  20. Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schlossmacher, M., Whaley J, Swindlehurst, C., McCormack, R., Wolfert, R., Selkoe, D., Lieberburg, I., and Schenk, D., 1992, Isolation and quantification of soluble Alzheimer’s ß-peptide from biological fluids, Nature 359: 325–327.PubMedCrossRefGoogle Scholar
  21. Shoji, M., Golde, T.E., Ghiso, J., Cheung, T.T., Estus, S., Shaffer, L.M., Cai X-D, McKay, D.M., Tintner, R., Frangione, B., and Younkin, S.G., 1992, Production of the Alzheimer amyloid 13-protein by normal proteolytic processing, Science 258: 126–129.PubMedCrossRefGoogle Scholar
  22. Sisodia, S.S., 1992, ß-Amyloid precursor protein cleavage by a membrane-bound pro ease Proc. Natl. Acad. Sci. USA 89:6075–6079.Google Scholar
  23. Sisodia, S.S., Koo, E.H., Beyreuther, K., Unterbeck, A., and Price, D.L., 1990, Evidence that fl-amyloid protein in Alzheimer’s disease is not derived by normal processing, Science 248: 492–495.PubMedCrossRefGoogle Scholar
  24. Slack, B.E., Nitsch, R.M., Livneh, E., Kunz, Jr,G.M., Breu, J., Eldar, H., and Wurtman, R.J., 1993, Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C., J. Biol. Chem. 268: 21097–21101.PubMedGoogle Scholar
  25. Vigo-Pelfrey, C., Lee, D., Keim, P., Lieberburg, I., and Schenk, D.B., 1993, Characterization of ß-amyloid from human cerebrospinal fluid, J. Neurochem. 61: 1965–1968.PubMedCrossRefGoogle Scholar
  26. Yankner, B.A., Duffy, L.K., and Kirschner, D.A., 1990, Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachikinin neuropeptides, Science 250: 279–282.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Roger M. Nitsch
    • 2
    • 1
  • Barbara E. Slack
    • 1
  • Steven A. Farber
    • 1
  • Meihua Deng
    • 1
  • Paul R. Borghesani
    • 1
  • Richard J. Wurtman
    • 1
  • John H. Growdon
    • 2
  1. 1.Department of Brain and Cognitive SciencesMassachusetts Institute of Technology E25-604CambridgeUSA
  2. 2.Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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