Skip to main content
SpringerLink
Log in

Stress kinases involved inTau phosphorylation in alzheimer’s disease, tauopathies and APP transgenic mice

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Hyperphosphorylation and accumulation oftau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer’s disease (AD) and other tauopathies, including Pick’s disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in thetau gene (FTDP-17-tau). Recent studies have shown increased expression of select active kinases, including stress-activated kinase, c-JunN-terminal kinase (SAPK/JNK) and kinase p38 in brain homogenates in all thetau opathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylatedtau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylatedtau have the capacity to phosphorylate recombinattau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated SAPK/JNK and p38 in association with hyperphosphorylated tau containing neurites have been observed around ßA4 amyloid deposits in the brain of transgenic mice (Tg2576) carrying the double APP Swedish mutation. These findings suggest that ßA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylatetau in neurites surrounding amyloid deposits. Reduction in the amyloid burden and decreased numbers of amyloid plaques but not of neurofibrillary degeneration has been observed in the brain of two AD patients who participated in an amyloid-ß immunization trial. Activation of stress kinases SAPK/JNK and p38 were reduced together with decreasedtau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques. These findings support the amyloid cascade hypothesis oftau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anderton BH, J Betts, WP Blackstock, JP Brion, S Chapman, J Connell, R Dayanandan, JM Gallo, G Gibb, DP Hanger, M Hutton, E Kardalinou, K Leroy, S Lovestone, T Mack, CH Reynolds and M van Slegtenhorst (2001) Sites of phosphorylation intau and factors affecting their regulation.Biochem. Soc. Symp. 67, 73–80.

    PubMed  CAS  Google Scholar 

  • Atzori C, B Ghetti, R Piva, AN Srinivasan, P Zolo, MB Delisle, SS Mirra and A Migheli (2001) Activation of the JNK/p38 pathway occurs in diseases characterized bytau protein pathology and is related totau phosphorylation but not to apoptosis.J. Neuropathol. Exp. Neurol. 60, 1190–1197.

    PubMed  CAS  Google Scholar 

  • Avila J, F Lim, F Moreno, C Belmonte and AC Cuello (2002)Ta u function and dysfunction in neurons, its role in neurodegenera-tive disorders.Mol. Neurobiol. 25, 213–231.

    Article  PubMed  CAS  Google Scholar 

  • Behl C (1999) AD and oxidative stress, implications for novel therapeutic approaches.Progr. Neurobiol. 57, 301–323.

    Article  CAS  Google Scholar 

  • Bertram L and R Tanzi (2003) Genetics of Alzheimer’s disease, In:Neurodegeneration, the Molecular Pathology of Dementia and Movement Disorders (Dickson D, Ed.) (ISN. Neuropath. Press, Basel), pp 40–46.

    Google Scholar 

  • Blanchard V, S Moussaoui, C Czech, N Touchet, B Bonici, M Planche, T Canton, I Jedidi, M Gohin, O Wirths, TA Bayer, D Langui, C Duyckaerts, G Tremp and L Pradier (2003) Time sequence of maturation of dystrophic neurites associated with Aß deposits in APP/PS1 transgenic mice.Exp. Neurol. 184, 247–263.

    Article  PubMed  CAS  Google Scholar 

  • Borchelt DR, T Ratovitsi, J van Lare, MK Lee, V Gozales, NA Jenkins, NG Copeland, DL Price and SS Sisodia (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.Neuron 19, 939–945.

    Article  PubMed  CAS  Google Scholar 

  • Bozyczko-Coyne D, TM O’Kane, ZL Wu, P Dobrzanski, S Murphy, JL Vaught and RW Scott (2001) CEP-1347/KT-7515, an inhibitor of SAPK/JNK pathway activity, promotes survival and blocks multiple events associated with Aß-induced cortical neuron apoptosis.J. Neurochem. 77, 849–863.

    Article  PubMed  CAS  Google Scholar 

  • Buée-Scherrer V and M Goedert (2002) Phosphorylation of micro-tubule-associated proteintau by stress-activated protein kinases in intact cells.FEBS Lett. 515, 151–154.

    Article  PubMed  Google Scholar 

  • Buée L, T Bussière, V Buée-Scherrer, A Delacourte and PR Hof (2000) Tau protein isoforms, phosphorylation and role in neu-rodegenerative disorders.Brain Res. Rev. 33, 95–130.

    Article  PubMed  Google Scholar 

  • Daniels WM, J Hendricks, R Salie and JJ Taljaard (2001) The role of MAP-kinase superfamily in ß-amyloid toxicity.Metab. Brain Dis. 16, 175–185.

    Article  PubMed  CAS  Google Scholar 

  • Duyckaerts C and DW Dickson (2003) Neuropathology of Alzheimer’s disease, In,Neurodegeneration, the Molecular Pathology of Dementia and Movement Disorders (Dickson D, Ed.) (ISN Neuropath. Press, Basel), pp 47–68.

    Google Scholar 

  • Ferrer I, R Blanco, M Carmona and B Puig (2001a) Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed intau deposits in neurons and glial cells intauopathies.J. Neural Transm. 108, 1397–1415.

    Article  PubMed  CAS  Google Scholar 

  • Ferrer I, R Blanco, M Carmona and B Puig (2001b) Phosphorylated c-Myc expression in Alzheimer disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration.Neuropathol. Appl. Neurobiol. 27, 343–351.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ferrer I, M Barrachina, M Tolnay, MJ Rey, N Vidal, M Carmona, R Blanco and B Puig (2003a) Phosphorylated protein kinases associated with neuronal and glialtau deposits in argyrophilic grain disease.Brain Pathol. 13, 62–78.

    PubMed  CAS  Google Scholar 

  • Ferrer I, P Pastor, MJ Rey, E Muñoz, B Puig, E Pastor, R Oliva and E Tolosa (2003b) Tau phosphorylation and kinase activation in familialtauopathy linked to delN296 mutation.Neuropathol. Appl. Neurobiol. 29, 23–34.

    Article  PubMed  CAS  Google Scholar 

  • Ferrer I, M Boada-Rovira, ML Sanchez-Guerra, MJ Rey and F Costa-Jussa (2004a) Neuropathology and pathogenesis of encephalitis following amyloid-ß immunization in Alzheimer’s disease.Brain Pathol. 14, 11–20.

    PubMed  CAS  Google Scholar 

  • Ferrer I, I Hernandez, B Puig, MJ Rey, M Ezquerra, E Tolosa and M Boada (2004b) Ubiquitin-negative mini-Pick-like bodies in the dentate gyrus in P301Ltauopathy.J. Alzheimer Dis. (in press).

  • Fogarty MP, EJ Downer and V Campbell (2003) A role for c-Jun N-terminal kinase 1 (JNK-1), but not JNK2, in the beta-amyloid-mediated stabilization of protein p53 and induction of the apop-totic cascade in cultured cortical neurons.Biochem. J. 371, 789–798.

    Article  PubMed  CAS  Google Scholar 

  • Furuta A, DL Price, CA Pardo, JC Troncoso, ZS Xu, N Taniguchi and LJ Martin (1995) Localization of superoxide dismutases in Alzheimer’s disease and Down’s syndrome neocortex and hippocampus.Am. J. Pathol. 146, 357–362.

    PubMed  CAS  Google Scholar 

  • Games D, D Adams, R Alessandrini, R Barbour, P Berthelette, C Blackwell, T Carr, J Clemens, T Donaldson and F Gillespie (1995) Alzheimer-type neuropathology in transgenic mice over-expressing V717F beta-amyloid precursor protein.Nature 349, 704–706.

    Google Scholar 

  • Ghetti B, ML Hutton and ZK Wszolek (2003) Frontotemporal dementia and parkinsonism linked to chromosome 17 associated withtau gene mutations (FTDP-17T), In:Neurodegeneration, The Molecular Pathology of Dementia and Movement Disorders (Dickson D, Ed.) (ISN. Neuropath. Press, Basel), pp 86–102.

    Google Scholar 

  • Goedert M, M Hasegawa, R Jakes, S Lawler, A Cuenda and P Cohen (1997) Phosphorylation of microtubule-associated proteintau by stress-activated protein kinases.FEBS Lett. 409, 57–62.

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Ramos A, J Diaz-Nido, MA Smith, G Perry and J Avila (2003) Effect of the lipid peroxidation product acrolein ontau phosphorylation in neural cells.J. Neurosci. Res. 71, 863–870.

    Article  PubMed  CAS  Google Scholar 

  • Hartzler AW, X Zhu, SL Siedlak, RJ Castellani, J Avila, G Perry and MA Smith (2002) The p38 pathway is activated in Pick disease and progressive supranuclear palsy, a mechanistic link between mitogenic pathways, oxidative stress andtau.Neurobiol. Aging 23, 855–859.

    Article  PubMed  CAS  Google Scholar 

  • Hensley K, RA Floyd, NY Zheng, R Nael, KA Robinson, X Nguyen, QN Pye, CA Stewart, J Geddes, WR Markesbery, E Patel, GV Johnson and G Bing (1999) p38 kinase is activated in the Alzheimer’s disease brain.J. Neurochem. 72, 2053–2058.

    Article  PubMed  CAS  Google Scholar 

  • Herreman A, L Serneels, W Annaert, D Collen, L Schoonjans and B De Strooper (2000) Total inactivation of ?-secretase activity in presenilin-deficient embryonic stem cells.Nat. Cell Biol. 2, 461–462.

    Article  PubMed  CAS  Google Scholar 

  • Holcomb L, MN Gordon, E McGowan, X Yu, S Benkovic, P Janyzen, K Wright, I Saad, R Mueller, D Morgan, S Sanders, C Zehr, K O’Campo, J Hardy, CM Prada, C Eckman, S Younkin, K Hsiao and K Duff (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenelin 1 transgenes.Nat. Med. 4, 97–100.

    Article  PubMed  CAS  Google Scholar 

  • Hsiao K, P Chapman, S Nilsen, C Exkman, Y Harigaya, S Younkin, F Yang and G Cole (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.Science 274, 99–102.

    Article  PubMed  CAS  Google Scholar 

  • Ingram EM and MG Spillantini (2002)Ta u gene mutations, dissecting the pathogenesis of FTDP-17.Trends Mol. Med. 8, 556–562.

    Article  Google Scholar 

  • Irizarry MC, M McNamara, K Fedorchak, K Hsia and BT Hyman (1997a) APPSw transgenic mice develop age-related Aß deposits and neuropil abnormalities, but no neuronal loss in CA1.J. Neuropathol. Exp. Neurol. 56, 965–973.

    Article  PubMed  CAS  Google Scholar 

  • Irizarry MC, F Soriano, M McNamara, KJ Page, D Schenk, D Games and BT Hyman (1997b) Aß deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse.J. Neurosci. 17, 7053–7059.

    PubMed  CAS  Google Scholar 

  • Jang JH and YJ Surth (2002) ß-amyloid induces oxidative DNA damage and cell death through activation of c-Jun N terminal kinase.Ann. NY Acad. Sci. 973, 228–236.

    Article  PubMed  CAS  Google Scholar 

  • Jenkins SM, M Zinnerman, C Garner and GV Johnson (2000) Modulation oftau phosphorylation and intracellular localization by cellular stress.Biochem. J. 345 part 2, 263–270.

    Article  PubMed  CAS  Google Scholar 

  • Knowles RB, J Chin, CT Ruff and BT Hyman (1999) Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibril-lary tangles, implications for MAP kinase activation in Alzheimer’s disease.J. Neuropathol. Exp. Neurol. 58, 1090–1098.

    Article  PubMed  CAS  Google Scholar 

  • Kruman I, AJ Bruce-Keller, D Brdeesen, G Waeg and MP Mattson (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci.17, 5089–5100.

    PubMed  CAS  Google Scholar 

  • Lee MVY, M Goedert and JQ Trojanowski (2001) Neurodegenerativetauopathies.Annu. Rev. Neurosci. 24, 1121–1159.

    Article  PubMed  CAS  Google Scholar 

  • Lovestone S and CH Reynolds (1997) The phosphorylation oftau: a critical stage in neurodevelopment and neurodegenerative processes.Neuroscience 78, 309–324.

    Article  PubMed  CAS  Google Scholar 

  • Mark RJ, MA Lowell, WR Markesbery, K Uchida and MP Mattson (1997) A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid ß-peptide.J. Neurochem. 68, 255–264.

    PubMed  CAS  Google Scholar 

  • Markesberry WR and JM Carney (1999) Oxidative alterations in Alzheimer’s disease.Brain Pathol. 9, 133–146.

    Google Scholar 

  • Masliah E, A Sisk, M Mallory and D Games (2001) Neurofibrillary pathology in transgenic mice overexpressing V717F ß-amyloid precursor protein.J. Neuropathol. Exp. Neurol. 60, 357–368.

    PubMed  CAS  Google Scholar 

  • McGowan E, F Pickord and DW Dickson (2003) Alzheimer animal models, models of Aß deposition in transgenic mice, In:Neurodegeneration, The Molecular Pathology of Dementia and Movement Disorders (Dickson D, Ed.) (ISN. Neuropath. Press, Basel), pp 74–79.

    Google Scholar 

  • Morishima Y, Y Gotoh, J Zieg, T Barrett, H Takano, R Flavell, RJ Davis, Y Shirasaki and ME Greenberg (2001) ß-amyloid induces neuronal apopotosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand.J. Neurosci. 21, 7551–7560.

    PubMed  CAS  Google Scholar 

  • Nicoll JAR, D Wilkinson, C Holmes, O Steart, H Markham and RO Weller (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-ß peptide, a case report.Nat. Med. 9, 4448–4452.

    Article  CAS  Google Scholar 

  • Nunomura A, G Perry, MA Papolla, R Wade, K Hirai, S Ciba and MA Smith (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease.J. Neurosci. 19, 1959–1964.

    PubMed  CAS  Google Scholar 

  • Nunomura A, G Perry, G Aliev, K Hiari, A Takeda, EK Balraj, PK Jones, H Ghanbari, T Wataya, S Shimohama, S Chiba, CS Atwood, RB Petersen and MA Smith (2001) Oxidative damage is the earliest event in Alzheimer’s disease.J. Neuropathol. Exp. Neurol. 60, 759–767.

    PubMed  CAS  Google Scholar 

  • Obaya AJ, MK Mateyak and JM Sedivy (1999) Mysterious liaisons, the relationship between c-Myc and the cell cycle.Oncogene 18, 2934–2941.

    Article  PubMed  CAS  Google Scholar 

  • Odetti P, S Garibaldi, R Norese, G Angelini, L Marinelli, S Valentini, S Menini, N Traverso, D Zaccheo, S Siedlak, G Perry, MA Smith and M Tabaton (2000) Lipoperxidation is selectively involved in progressive supranuclear palsy.J. Neuropathol. Exp. Neurol. 59, 393–397.

    PubMed  CAS  Google Scholar 

  • Pappolla MA, RA Omar, KS Kim and NK Robakis (1992) Immunohistochemical evidence of oxidative stress in Alzheimer’s disease.Am. J. Pathol. 140, 621–628.

    PubMed  CAS  Google Scholar 

  • Pappolla MA, YJ Chyan, RA Omar, K Hsiao, G Perry, MA Smith and P Bozner (1998) Evidence of oxidative stress andin vivo neurotoxicity of ß-amyloid in a transgenic mouse model of Alzheimer’s disease, a chronic oxidative paradigm for testing antioxidant therapiesin vivo.Am.. J. Pathol. 152, 871–877.

    PubMed  CAS  Google Scholar 

  • Pei JJ, E Braak, H Braak, K Grundque-Iqbal, W Winblad and RF Cowburn (2001) Localization of active forms of c-Jun kinase (JNK) and p38 kinase in Alzheimer’s disease brains at different stages of neurofibrillary degeneration.J. Alzheimer’s Dis. 3, 41–48.

    CAS  Google Scholar 

  • Perry G, RJ Castellani, K Hirai and MA Smith (1998) Reactive oxygen species mediate cellular damage in Alzheimer’s disease.J. Alzheimer Dis. 1, 45–55.

    CAS  Google Scholar 

  • Perry G, H Roder, A Nunomura, A Takeda, AL Friedlich, X Zhu, AL Raina, N Holbrook, SL Siedlak, PLR Harris and MA Smith (1999) Activation of extracellular receptor kinase (ERK) in Alzheimer’s disease links oxidative stress to abnormaltau phos-phorylation.NeuroReport 10, 2411–2415.

    PubMed  CAS  Google Scholar 

  • Puig B, T Gómez-Isla, E Ribe, M Cuadrado and I Ferrer (2004a) Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P) links oxidative stress andtau hyperphosphorylation in neurites surrounding Aß plaques in APP Tg2576 mice.Neuropathol. Appl. Neurobiol. (in press).

  • Puig B, F Viñals and I Ferrer (2004b) Active stress kinase p38 enhances and perpetuates abnormaltau phosphorylation and deposition in Pick’s disease.Acta Neuropathol. (in press).

  • Reynolds CH, AR Nebreda, GM Gibb, MA Utton and BH Anderton (1997a) Reactivating kinase/p38 phosphorylatestau proteinin vitro.J. Neurochem. 69, 191–198.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds CH, MA Utton, GM Gibb, A Yates and BH Anderton (1997b) Stress-activated protein kinase/c-JunN-terminal kinase phosphorylatestau protein.J. Neurochem. 68, 1736–1744.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds CH, JC Betts, WP Blackstock, AR Nebreda and BH Anderton (2000) Phosphorylation sites ontau identified by nano-electrospray mass spectrometry, differencesin vitro between the mitogen-activated protein kinases ERK2, c-JunN-terminal kinase and p38, and glycogen synthase kinase-3ß.J. Neurochem. 74, 1587–1595.

    Article  PubMed  CAS  Google Scholar 

  • Savage MJ, YG Lin, JR Ciallella, DG Flood and RW Scott (2002) Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition.J. Neurosci. 22, 3376–3385.

    PubMed  CAS  Google Scholar 

  • Selznick LA, DM Holtnman, BH Han, M Gökden, AN Srinavasan, EM Jonson and KA Roth (1999) In situ immunodetection of neu-ronal caspase-3 activation in Alzheimer’s disease.J. Neuropathol. Exp. Neurol. 58, 1020–1026.

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, LM Sayre, MP Vitek, VM Monnier and G Perry (1995) Early AGE in Alzheimer’s disease.Nature 374, 316.

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, K Hirai, K Hsiao, MA Pappolla, PL Harris, SL Siedlak, M Tabaton and G Perry (1998) Amyloid-ß deposition in Alzheimer transgenic mice is associated with oxidative stress.J. Neurochem. 70, 2212–2215.

    PubMed  CAS  Google Scholar 

  • Smith MA, CA Rottkamp, A Nunomura, AK Raina and G Perry (2000) Oxidative stress in Alzheimer’s disease.Biochem. Biophys. Acta 1502, 139–144.

    PubMed  CAS  Google Scholar 

  • Spillantini MG and M Goedert (1998)Ta u protein pathology in neurodegenerative diseases.Trends Neurosci. 21, 428–433.

    Article  PubMed  CAS  Google Scholar 

  • Sturchler-Pierrat C, D Abramowski, M Duke, KH Wiederhold, C Mistl, S Rothacher, B Ledermann, K Burki, P Frey, PA Paganetti, C Waridel, ME Calhoun, M Jucker, A Probst, M Staufenbiel and B Sommer (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc. Natl. Acad. Sci. USA 94, 13287–13292.

    Article  PubMed  CAS  Google Scholar 

  • Sun A, M Liu, XV Nguyen and G Bing (2003) p38 MAP kinase is activated at early stages in Alzheimer’s disease brain.Exp. Neurol. 183, 394–405.

    Article  PubMed  CAS  Google Scholar 

  • Tamagno E, G Robino, A Obbili, P Bardini, M Aragno, M Parola and O Danni (2003) H2O2 and 4-hydroxynonenal mediate ß-amyloid-induced neuronal apoptosis by activating JNKs and p38 MAPKs.Exp. Neurol. 180, 144–155.

    Article  PubMed  CAS  Google Scholar 

  • Togo T, N Sahara, SH Yen, N Cookson, T Ishizawa, M Hutton, R De Silva, A Lees and DW Dickson (2002) Argyrophilic grain disease is a sporadic 4-repeat tauopathy.J. Neuropathol. Exp. Neurol. 61, 547–556.

    PubMed  CAS  Google Scholar 

  • Tomidokoro Y, Y Harigaya, E Matsubara, M Ikeda, T Kawarabayashi, T Shirao, K Ishiguro, K Okamoto, SG Younkin and M Shoji (2001) Brain Aß amyloidosis in APP(Sw) mice induces accumulation of presenilin-1 andtau.J. Pathol. 194, 500–506.

    Article  PubMed  CAS  Google Scholar 

  • Troy CM, SA Rabacchi, Z Xu, AC Maroney, TJ Connors, ML Shelanski and LA Greene (2001) Beta-amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation.J. Neurochem. 77, 157–164.

    Article  PubMed  CAS  Google Scholar 

  • Wei W, DD Norton, X Wang and JW Kusiak (2002a) Aß 17-42 in Alzheimer’s diseae actiavers JNK and caspase-8 leading to neu-ronal apoptosis.Brain 125, 2036–2043.

    Article  PubMed  Google Scholar 

  • Wei W, X Wang and JW Kusiak (2002b) Signaling events in amyloid ß-peptide-induced neuronal death and insulin-like growth factor I protection.J. Biol. Chem. 277, 17649–17656.

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, P Nadeau, W Song, D Donoviel, M Yuan, A Bernstein and BA Yankner (2000) Presenilins are required for ?-secretase cleavage of ß-APP and transmembrane cleavage of Notch-1.Nat. Cell Biol. 2, 463–465.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, CA Rottkamp, H Boux, A Takeda, G Perry and MA Smith (2000) Activation of p38 kinase linkstau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease.J. Neuropathol. Exp. Neurol. 59, 880–888.

    PubMed  CAS  Google Scholar 

  • Zhu X, RJ Castellani, A Takeda, A Nunomura, CS Atwood, G Perry and MA Smith (2001a) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer’s disease, the two hit hypothesis.Mech. Ageing Dev. 123, 39–46.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, AK Raina, CA Rottkamp, G Aliev, G Perry, H Boux and MA Smith (2001b) Activation and redistribution of c-Jun N-ter-minal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease.J. Neurochem. 76, 435–441.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, CA Rottkamp, A Hartzler, Z Sun, A Takeda, H Boux, S Shimohama, G Perry and MA Smith (2001c) Activation of MKK6, an upstream activator of p38, in Alzheimer’s disease.J. Neurochem. 79, 311–318.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, HG Lee, AK Raina, G Perry and MA Smith (2002) The role of mitogen-activated protein kinase pathways in Alzheimer’s disease.Neurosignals 11, 270–281.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, O Ogawa, Y Wang, G Perry and MA Smith (2003a) JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer’s disease.J. Neurochem. 85, 87–93.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, AK Raina, HG Lee, M Chao, A Nunomura, M Tabaton, RB Petersen, G Perry and MA Smith (2003b) Oxidative stress and neuronal adaptation in Alzheimer disease, the role of SAPK pathways.Antioxid. Redox Signal 5, 571–576.

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Z Sun, HG Lee, SL Siedlak, G Perry and MA Smith (2003c) Distribution, levels, and activation of MEK1 in Alzheimer’s disease.J. Neurochem. 86, 136–142.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut de Neuropatologia, Servei Anatomia Patològica, Hospital de Bellvitge, Universitat de Barcelona, carrer Feixa Llarga sn, Hospitalet de Llobregat, 08907, Spain

    I. Ferrer

Authors
  1. I. Ferrer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. Ferrer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferrer, I. Stress kinases involved inTau phosphorylation in alzheimer’s disease, tauopathies and APP transgenic mice. neurotox res 6, 469–475 (2004). https://doi.org/10.1007/BF03033283

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033283

Keywords

Search

Navigation