Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease

Abstract

It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer’s disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Aβ42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Aβ generation, denotes a vicious feedforward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 91

1. 1.

   Alcock RA, Dey S, Chendil D, Inayat MS, Mohiuddin M, Hartman G, Chatfield LK, Gallicchio VS, Ahmed MM (2002 ) Farnesyltransferase inhibitor (L-744,832) restores TGF-beta type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2. Oncogene 21:7883–7890.

   Not in our library10.1038/sj.onc.1205948

2. 2.

   Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH (1996 ) In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta. J Neurochem 67:699–707.

   Not in our library10.1046/j.1471-4159.1996.67020699.x

3. 3.

   Arendt T, Holzer M, Grossmann A, Zedlick D, Brückner MK (1995 ) Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer’s disease. Neuroscience 68:5–18.

   Not in our library10.1016/0306-4522(95)00146-a

4. 4.

   Arendt T, Holzer M, Stöbe A, Gärtner U, Lüth HJ, Brückner MK, Ueberham U (2000 ) Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer’s disease that eventually results in cell death. Ann N Y Acad Sci 920:249–255.

   Not in our library10.1111/j.1749-6632.2000.tb06931.x

5. 5.

   Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993 ) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821.

   Not in our library10.1101/gad.7.5.812

6. 6.

   Balmanno K, Cook SJ (1999 ) Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene 18:3085–3097.

   Not in our library10.1038/sj.onc.1202647

7. 7.

   Barge RM, Dorrestijn J, Falkenburg JH, Willemze R, Maassen JA (1998 ) Unconventional rapid Erk1,2 activation is indispensable for proliferation of the growth factor-independent myeloid leukemic cell line KG1. Leukemia 12:699–704.

   Not in our library10.1038/sj.leu.2400991

8. 8.

   Blanchard BJ, devi Raghunandan R, Roder HM, Ingram VM (1994 ) Hyperphosphorylation of human TAU by brain kinase PK40erk beyond phosphorylation by cAMP-dependent PKA: relation to Alzheimer’s disease. Biochem Biophys Res Commun 200:187–194.

   Not in our library10.1006/bbrc.1994.1432

9. 9.

   Braak H, Braak E (1991 ) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259.

   Not in our library10.1007/bf00308809

10. 10.

    Braak H, Braak E (1995 ) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278.

    Not in our library10.1016/0197-4580(95)00021-6

11. 11.

    Busciglio J, Lorenzo A, Yeh J, Yankner BA (1995 ) beta-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–888.

    Not in our library10.1016/0896-6273(95)90232-5

12. 12.

    Busser J, Geldmacher DS, Herrup K (1998 ) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci 18:2801–2807.

    Not in our library10.1523/jneurosci.18-08-02801.1998

13. 13.

    Chang KA, Kim HS, Ha TY, Ha JW, Shin KY, Jeong YH, Lee JP, Park CH, Kim S, Baik TK, Suh YH (2006 ) Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration. Mol Cell Biol 26:4327–4338.

    Not in our library10.1128/mcb.02393-05

14. 14.

    Chaput D, Kirouac LH, Bell-Temin H, Stevens SM, Jr, Padmanabhan J (2012 ) SILAC-based proteomic analysis to investigate the impact of amyloid precursor protein expression in neuronal-like B103 cells. Electrophoresis 33:3728–3737.

    Not in our library10.1002/elps.201200251

15. 15.

    Cho JH, Johnson GV (2003 ) Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding. J Biol Chem 278:187–193.

    Not in our library10.1074/jbc.m206236200

16. 16.

    Cho JH, Johnson GV (2004 ) Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau’s ability to bind and stabilize microtubules. J Neurochem 88:349–358.

    Not in our library10.1111/j.1471-4159.2004.02155.x

17. 17.

    Copani A, Condorelli F, Caruso A, Vancheri C, Sala A, Giuffrida Stella AM, Canonico PL, Nicoletti F, Sortino MA (1999 ) Mitotic signaling by beta-amyloid causes neuronal death. FASEB J 13:2225–2234.

    Not in our library

18. 18.

    Cosgaya JM, Latasa MJ, Pascual A (1996 ) Nerve growth factor and ras regulate beta-amyloid precursor protein gene expression in PC12 cells. J Neurochem 67:98–104.

    Not in our library10.1046/j.1471-4159.1996.67010098.x

19. 19.

    Dabrowski A, Groblewski GE, Schäfer C, Guan KL, Williams JA (1997 ) Cholecystokinin and EGF activate a MAPK cascade by different mechanisms in rat pancreatic acinar cells. Am J Physiol 273:C1472–C1479.

    Not in our library10.1152/ajpcell.1997.273.5.c1472

20. 20.

    DeMattos RB, Cirrito JR, Parsadanian M, May PC, O’Dell MA, Taylor JW, Harmony JA, Aronow BJ, Bales KR, Paul SM, Holtzman DM (2004 ) ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41:193–202.

    Not in our library10.1016/s0896-6273(03)00850-x

21. 21.

    Dignam JD, Lebovitz RM, Roeder RG (1983 ) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–1489.

    Not in our library10.1093/nar/11.5.1475

22. 22.

    Dineley KT, Westerman M, Bui D, Bell K, Ashe KH, Sweatt JD (2001 ) Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer’s disease. J Neurosci 21:4125–4133.

    Not in our library10.1523/jneurosci.21-12-04125.2001

23. 23.

    Drewes G, Lichtenberg-Kraag B, Döring F, Mandelkow EM, Biernat J, Goris J, Dorée M, Mandelkow E (1992 ) Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 11:2131–2138.

    Not in our library10.1002/j.1460-2075.1992.tb05272.x

24. 24.

    Ekinci FJ, Malik KU, Shea TB (1999 ) Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration. J Biol Chem 274:30322–30327.

    Not in our library10.1074/jbc.274.42.30322

25. 25.

    Ferrer I, Blanco R, Carmona M, Ribera R, Goutan E, Puig B, Rey MJ, Cardozo A, Viñals F, Ribalta T (2001 ) Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. Brain Pathology 11:144–158.

    Not in our library10.1111/j.1750-3639.2001.tb00387.x

26. 26.

    Gärtner U, Holzer M, Arendt T (1999 ) Elevated expression of p21ras is an early event in Alzheimer’s disease and precedes neurofibrillary degeneration. Neuroscience 91:1–5.

    Not in our library10.1016/s0306-4522(99)00059-7

27. 27.

    Gärtner U, Holzer M, Heumann R, Arendt T (1995 ) Induction of p21ras in Alzheimer pathology. Neuroreport 6:1441–1444.

    Not in our library10.1097/00001756-199507100-00020

28. 28.

    Geryk-Hall M, Yang Y, Hughes DP (2010 ) Driven to death: inhibition of farnesylation increases Ras activity and promotes growth arrest and cell death [corrected]. Mol Cancer Ther 9:1111–1119.

    Not in our library10.1158/1535-7163.mct-09-0833

29. 29.

    Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA (1998 ) Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med 4:827–831.

    Not in our library10.1038/nm0798-827

30. 30.

    Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS (1999 ) Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F x DP, in B-amyloid-induced neuronal death. J Biol Chem 274:19011–19016.

    Not in our library10.1074/jbc.274.27.19011

31. 31.

    Glenner GG, Wong CW (1984 ) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122:1131–1135.

    Not in our library10.1016/0006-291x(84)91209-9

32. 32.

    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. (1991 ) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706.

    Not in our library10.1038/349704a0

33. 33.

    Goedert M, Cohen ES, Jakes R, Cohen P (1992 ) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer’s disease [corrected]. FEBS Lett 312:95–99.

    Not in our library10.1016/0014-5793(92)81418-l

34. 34.

    Goedert M, Jakes R, Crowther RA, Cohen P, Vanmechelen E, Vandermeeren M, Cras P (1994 ) Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer’s disease: identification of phosphorylation sites in tau protein. Biochem J 301:871–877.

    Not in our library10.1042/bj3010871

35. 35.

    Gold G, Bouras C, Kövari E, Canuto A, Glaria BG, Malky A, Hof PR, Michel JP, Giannakopoulos P (2000 ) Clinical validity of Braak neuropathological staging in the oldest-old. Acta Neuropathol 99:579–582.

    Not in our library10.1007/s004010051163

36. 36.

    Götz J, Chen F, van Dorpe J, Nitsch RM (2001 ) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495.

    Not in our library10.1126/science.1062097

37. 37.

    Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH (1992 ) Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett 147:58–62.

    Not in our library10.1016/0304-3940(92)90774-2

38. 38.

    Hardy J (1997 ) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159.

    Not in our library10.1016/s0166-2236(96)01030-2

39. 39.

    Hyman BT, Elvhage TE, Reiter J (1994 ) Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer’s disease. Am J Pathol 144:565–572.

    Not in our library

40. 40.

    Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T (2000 ) Neuron-specific phosphorylation of Alzheimer’s beta-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem 75:1085–1091.

    Not in our library10.1046/j.1471-4159.2000.0751085.x

Cited by papers we hold 3

• The duality of amyloid-β: its role in normal and Alzheimer’s disease states · 2024
  No notice
• Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines · 2020
  Not checked
• Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer · 2020
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.