Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Jul 19;91(15):7104–7108. doi: 10.1073/pnas.91.15.7104

Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation.

S M Greenberg 1, E H Koo 1, D J Selkoe 1, W Q Qiu 1, K S Kosik 1
PMCID: PMC44347  PMID: 8041753

Abstract

Biological effects related to cell growth, as well as a role in the pathogenesis of Alzheimer disease, have been ascribed to the beta-amyloid precursor protein (beta-APP). Little is known, however, about the intracellular cascades that mediate these effects. We report that the secreted form of beta-APP potently stimulates mitogen-activated protein kinases (MAPKs). Brief exposure of PC-12 pheochromocytoma cells to beta-APP secreted by transfected Chinese hamster ovary cells stimulated the 43-kDa form of MAPK by > 10-fold. Induction of a dominant inhibitory form of ras in a PC12-derived cell line prevented the stimulation of MAPK by secreted beta-APP, demonstrating the dependence of the effect upon p21ras. Because the microtubule-associated protein tau is hyperphosphorylated in Alzheimer disease, we sought and found a 2-fold enhancement in tau phosphorylation associated with the beta-APP-induced MAPK stimulation. In the ras dominant inhibitory cell line, beta-APP failed to enhance phosphorylation of tau. The data presented here provide a link between secreted beta-APP and the phosphorylation state of tau.

Full text

PDF
7104

Images in this article

7106Image
on p.7106
7106Image
on p.7106
7106Image
on p.7106
7107Image
on p.7107

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai H., Lee V. M., Otvos L., Jr, Greenberg B. D., Lowery D. E., Sharma S. K., Schmidt M. L., Trojanowski J. Q. Defined neurofilament, tau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2249–2253. doi: 10.1073/pnas.87.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Araki W., Kitaguchi N., Tokushima Y., Ishii K., Aratake H., Shimohama S., Nakamura S., Kimura J. Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun. 1991 Nov 27;181(1):265–271. doi: 10.1016/s0006-291x(05)81412-3. [DOI] [PubMed] [Google Scholar]
  3. Biernat J., Mandelkow E. M., Schröter C., Lichtenberg-Kraag B., Steiner B., Berling B., Meyer H., Mercken M., Vandermeeren A., Goedert M. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J. 1992 Apr;11(4):1593–1597. doi: 10.1002/j.1460-2075.1992.tb05204.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bramblett G. T., Goedert M., Jakes R., Merrick S. E., Trojanowski J. Q., Lee V. M. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron. 1993 Jun;10(6):1089–1099. doi: 10.1016/0896-6273(93)90057-x. [DOI] [PubMed] [Google Scholar]
  5. Cras P., Kawai M., Lowery D., Gonzalez-DeWhitt P., Greenberg B., Perry G. Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7552–7556. doi: 10.1073/pnas.88.17.7552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Drewes G., Lichtenberg-Kraag B., Döring F., Mandelkow E. M., Biernat J., Goris J., Dorée M., Mandelkow E. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 1992 Jun;11(6):2131–2138. doi: 10.1002/j.1460-2075.1992.tb05272.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goedert M., Cohen E. S., Jakes R., Cohen P. p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. FEBS Lett. 1992 Nov 2;312(1):95–99. doi: 10.1016/0014-5793(92)81418-l. [DOI] [PubMed] [Google Scholar]
  8. Goedert M., Jakes R., Crowther R. A., Six J., Lübke U., Vandermeeren M., Cras P., Trojanowski J. Q., Lee V. M. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5066–5070. doi: 10.1073/pnas.90.11.5066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hanger D. P., Mann D. M., Neary D., Anderton B. H. Tau pathology in a case of familial Alzheimer's disease with a valine to glycine mutation at position 717 in the amyloid precursor protein. Neurosci Lett. 1992 Oct 12;145(2):178–180. doi: 10.1016/0304-3940(92)90016-z. [DOI] [PubMed] [Google Scholar]
  10. Hasegawa M., Morishima-Kawashima M., Takio K., Suzuki M., Titani K., Ihara Y. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J Biol Chem. 1992 Aug 25;267(24):17047–17054. [PubMed] [Google Scholar]
  11. Hung A. Y., Koo E. H., Haass C., Selkoe D. J. Increased expression of beta-amyloid precursor protein during neuronal differentiation is not accompanied by secretory cleavage. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9439–9443. doi: 10.1073/pnas.89.20.9439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hyman B. T., Elvhage T. E., Reiter J. Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease. Am J Pathol. 1994 Mar;144(3):565–572. [PMC free article] [PubMed] [Google Scholar]
  13. Joachim C., Games D., Morris J., Ward P., Frenkel D., Selkoe D. Antibodies to non-beta regions of the beta-amyloid precursor protein detect a subset of senile plaques. Am J Pathol. 1991 Feb;138(2):373–384. [PMC free article] [PubMed] [Google Scholar]
  14. Kosik K. S. Alzheimer's disease: a cell biological perspective. Science. 1992 May 8;256(5058):780–783. doi: 10.1126/science.1589757. [DOI] [PubMed] [Google Scholar]
  15. Kosik K. S., Orecchio L. D., Binder L., Trojanowski J. Q., Lee V. M., Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron. 1988 Nov;1(9):817–825. doi: 10.1016/0896-6273(88)90129-8. [DOI] [PubMed] [Google Scholar]
  16. Kowall N. W., Beal M. F., Busciglio J., Duffy L. K., Yankner B. A. An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7247–7251. doi: 10.1073/pnas.88.16.7247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  18. Lantos P. L., Luthert P. J., Hanger D., Anderton B. H., Mullan M., Rossor M. Familial Alzheimer's disease with the amyloid precursor protein position 717 mutation and sporadic Alzheimer's disease have the same cytoskeletal pathology. Neurosci Lett. 1992 Mar 30;137(2):221–224. doi: 10.1016/0304-3940(92)90408-y. [DOI] [PubMed] [Google Scholar]
  19. Ledesma M. D., Correas I., Avila J., Díaz-Nido J. Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer's disease. FEBS Lett. 1992 Aug 17;308(2):218–224. doi: 10.1016/0014-5793(92)81278-t. [DOI] [PubMed] [Google Scholar]
  20. Lee V. M., Balin B. J., Otvos L., Jr, Trojanowski J. Q. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991 Feb 8;251(4994):675–678. doi: 10.1126/science.1899488. [DOI] [PubMed] [Google Scholar]
  21. Lichtenberg-Kraag B., Mandelkow E. M., Biernat J., Steiner B., Schröter C., Gustke N., Meyer H. E., Mandelkow E. Phosphorylation-dependent epitopes of neurofilament antibodies on tau protein and relationship with Alzheimer tau. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5384–5388. doi: 10.1073/pnas.89.12.5384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lu Q., Soria J. P., Wood J. G. p44mpk MAP kinase induces Alzheimer type alterations in tau function and in primary hippocampal neurons. J Neurosci Res. 1993 Jul 1;35(4):439–444. doi: 10.1002/jnr.490350411. [DOI] [PubMed] [Google Scholar]
  23. Lu Q., Wood J. G. Functional studies of Alzheimer's disease tau protein. J Neurosci. 1993 Feb;13(2):508–515. doi: 10.1523/JNEUROSCI.13-02-00508.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mandelkow E. M., Drewes G., Biernat J., Gustke N., Van Lint J., Vandenheede J. R., Mandelkow E. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 1992 Dec 21;314(3):315–321. doi: 10.1016/0014-5793(92)81496-9. [DOI] [PubMed] [Google Scholar]
  25. Masliah E., Mallory M., Ge N., Saitoh T. Amyloid precursor protein is localized in growing neurites of neonatal rat brain. Brain Res. 1992 Oct 16;593(2):323–328. doi: 10.1016/0006-8993(92)91329-d. [DOI] [PubMed] [Google Scholar]
  26. Mattson M. P., Cheng B., Culwell A. R., Esch F. S., Lieberburg I., Rydel R. E. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron. 1993 Feb;10(2):243–254. doi: 10.1016/0896-6273(93)90315-i. [DOI] [PubMed] [Google Scholar]
  27. Milward E. A., Papadopoulos R., Fuller S. J., Moir R. D., Small D., Beyreuther K., Masters C. L. The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron. 1992 Jul;9(1):129–137. doi: 10.1016/0896-6273(92)90228-6. [DOI] [PubMed] [Google Scholar]
  28. Moya K. L., Benowitz L. I., Schneider G. E., Allinquant B. The amyloid precursor protein is developmentally regulated and correlated with synaptogenesis. Dev Biol. 1994 Feb;161(2):597–603. doi: 10.1006/dbio.1994.1055. [DOI] [PubMed] [Google Scholar]
  29. Oltersdorf T., Fritz L. C., Schenk D. B., Lieberburg I., Johnson-Wood K. L., Beattie E. C., Ward P. J., Blacher R. W., Dovey H. F., Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144–147. doi: 10.1038/341144a0. [DOI] [PubMed] [Google Scholar]
  30. Pelech S. L., Sanghera J. S. Mitogen-activated protein kinases: versatile transducers for cell signaling. Trends Biochem Sci. 1992 Jun;17(6):233–238. doi: 10.1016/s0968-0004(00)80005-5. [DOI] [PubMed] [Google Scholar]
  31. Podlisny M. B., Stephenson D. T., Frosch M. P., Lieberburg I., Clemens J. A., Selkoe D. J. Synthetic amyloid beta-protein fails to produce specific neurotoxicity in monkey cerebral cortex. Neurobiol Aging. 1992 Sep-Oct;13(5):561–567. doi: 10.1016/0197-4580(92)90056-4. [DOI] [PubMed] [Google Scholar]
  32. Razzaboni B. L., Papastoitsis G., Koo E. H., Abraham C. R. A calcium-stimulated serine protease from monkey brain degrades the beta-amyloid precursor protein. Brain Res. 1992 Sep 4;589(2):207–216. doi: 10.1016/0006-8993(92)91279-n. [DOI] [PubMed] [Google Scholar]
  33. Robbins D. J., Cheng M., Zhen E., Vanderbilt C. A., Feig L. A., Cobb M. H. Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6924–6928. doi: 10.1073/pnas.89.15.6924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Roch J. M., Shapiro I. P., Sundsmo M. P., Otero D. A., Refolo L. M., Robakis N. K., Saitoh T. Bacterial expression, purification, and functional mapping of the amyloid beta/A4 protein precursor. J Biol Chem. 1992 Feb 5;267(4):2214–2221. [PubMed] [Google Scholar]
  35. Roder H. M., Eden P. A., Ingram V. M. Brain protein kinase PK40erk converts TAU into a PHF-like form as found in Alzheimer's disease. Biochem Biophys Res Commun. 1993 Jun 15;193(2):639–647. doi: 10.1006/bbrc.1993.1672. [DOI] [PubMed] [Google Scholar]
  36. Saitoh T., Sundsmo M., Roch J. M., Kimura N., Cole G., Schubert D., Oltersdorf T., Schenk D. B. Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts. Cell. 1989 Aug 25;58(4):615–622. doi: 10.1016/0092-8674(89)90096-2. [DOI] [PubMed] [Google Scholar]
  37. Schubert D., Jin L. W., Saitoh T., Cole G. The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion. Neuron. 1989 Dec;3(6):689–694. doi: 10.1016/0896-6273(89)90237-7. [DOI] [PubMed] [Google Scholar]
  38. Shoemaker D. G., Bender C. A., Gunn R. B. Sodium-phosphate cotransport in human red blood cells. Kinetics and role in membrane metabolism. J Gen Physiol. 1988 Oct;92(4):449–474. doi: 10.1085/jgp.92.4.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Siman R., Card J. P., Nelson R. B., Davis L. G. Expression of beta-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron. 1989 Sep;3(3):275–285. doi: 10.1016/0896-6273(89)90252-3. [DOI] [PubMed] [Google Scholar]
  40. Stephenson D. T., Rash K., Clemens J. A. Amyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat. Brain Res. 1992 Oct 9;593(1):128–135. doi: 10.1016/0006-8993(92)91274-i. [DOI] [PubMed] [Google Scholar]
  41. Thomas S. M., DeMarco M., D'Arcangelo G., Halegoua S., Brugge J. S. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell. 1992 Mar 20;68(6):1031–1040. doi: 10.1016/0092-8674(92)90075-n. [DOI] [PubMed] [Google Scholar]
  42. Trojanowski J. Q., Mawal-Dewan M., Schmidt M. L., Martin J., Lee V. M. Localization of the mitogen activated protein kinase ERK2 in Alzheimer's disease neurofibrillary tangles and senile plaque neurites. Brain Res. 1993 Aug 6;618(2):333–337. doi: 10.1016/0006-8993(93)91286-2. [DOI] [PubMed] [Google Scholar]
  43. Van Nostrand W. E., Wagner S. L., Suzuki M., Choi B. H., Farrow J. S., Geddes J. W., Cotman C. W., Cunningham D. D. Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Nature. 1989 Oct 12;341(6242):546–549. doi: 10.1038/341546a0. [DOI] [PubMed] [Google Scholar]
  44. Wallace W., Ahlers S. T., Gotlib J., Bragin V., Sugar J., Gluck R., Shea P. A., Davis K. L., Haroutunian V. Amyloid precursor protein in the cerebral cortex is rapidly and persistently induced by loss of subcortical innervation. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8712–8716. doi: 10.1073/pnas.90.18.8712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wang R., Meschia J. F., Cotter R. J., Sisodia S. S. Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells. J Biol Chem. 1991 Sep 5;266(25):16960–16964. [PubMed] [Google Scholar]
  46. Watanabe A., Hasegawa M., Suzuki M., Takio K., Morishima-Kawashima M., Titani K., Arai T., Kosik K. S., Ihara Y. In vivo phosphorylation sites in fetal and adult rat tau. J Biol Chem. 1993 Dec 5;268(34):25712–25717. [PubMed] [Google Scholar]
  47. Weidemann A., König G., Bunke D., Fischer P., Salbaum J. M., Masters C. L., Beyreuther K. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 1989 Apr 7;57(1):115–126. doi: 10.1016/0092-8674(89)90177-3. [DOI] [PubMed] [Google Scholar]
  48. Whitson J. S., Selkoe D. J., Cotman C. W. Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science. 1989 Mar 17;243(4897):1488–1490. doi: 10.1126/science.2928783. [DOI] [PubMed] [Google Scholar]
  49. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  50. Yankner B. A., Duffy L. K., Kirschner D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990 Oct 12;250(4978):279–282. doi: 10.1126/science.2218531. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES