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The Induction of the TNFα Death Domain Signaling Pathway in Alzheimer's Disease Brain

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Abstract

The tumor necrosis factor-α death domain pathway contributes to cellular degeneration in a variety of conditions. This study investigates the hypothesis that this death domain pathway is progressively induced in the brain during the progression of Alzheimer's disease (AD). AD cases had increased levels of proapoptotic markers including tumor necrosis factor-α (TNFα), TNF receptor type 1 (TNF-R1), TNF receptor–associated death domain (TRADD), and caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3 times higher than transitional cases. In striking contrast, potentially neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain-like interleukin-1β–converting enzyme (FLICE) inhibitor protein (FLIP) were decreased in AD as compared with age-matched control cases (P < .01). Overall, there was an elevation in proapoptotic elements, including a 5-fold increase in TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate to increased degenerative potential because the downstream effector caspase-3 and product of the TNF pathway was also increased in parallel with enhanced TNF proapoptotic conditions. Our findings suggest that the TNF death receptor pathway and caspases are activated in the early stages of neuronal degeneration in AD.

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REFERENCES

  1. Khachaturian, Z. S. 1985. Diagnosis of Alzheimer's disease. Arch. Neurol. 42:1097–1105.

    PubMed  Google Scholar 

  2. Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., van Belle, G., and Berg, L. 1991. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479–486.

    PubMed  Google Scholar 

  3. Forloni, G., Chiesa, R., Smiroldo, S., Verga, L., Salmona, M., Tagliavini, F., and Angeretti, N. 1993. Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25–35. Neuroreport 4:523–526.

    PubMed  Google Scholar 

  4. Loo, D. T., Copani, A., Pike, C. J., Whittemore, R. E., Walencewicz, A. J., and Cotman, C. W. 1993. Apoptosis is induced by β-amyloid in cultured central nervous system neurons. Proc. Natl. Acad. Sci. USA 90:7951–7955.

    PubMed  Google Scholar 

  5. Su, J. H., Anderson, A. J., Cummings, B. J., and Cotman, C. W. 1994. Immunohistochemical evidence for apoptosis in Alzheimer's disease. Neuroreport 5:2529–2533.

    PubMed  Google Scholar 

  6. Marks, N. and Berg, M. J. 1999. Recent advances on neuronal caspases in development and neurodegeneration. Neurochem. Int. 35:195–220.

    PubMed  Google Scholar 

  7. Cotman C. W., Ivins K., and Anderson A. J. 1999. Apoptosis in Alzheimer's disease. Pages 347–358, in Terry, R., Katzman, R., Bick, K., and Sisodia, S. (eds.), Alzheimer's Disease, 2nd Ed. Lippincott, Williams & Wilkins, New York.

    Google Scholar 

  8. Wang, S., Rosengren, L. E., Franlund, M., Hamberger, A., and Haglid, K. G. 1999. Bcl-2 expression regulates cell sensitivity to S100beta-mediated apoptosis. Brain. Res. Mol. Brain. Res. 70:167–176.

    PubMed  Google Scholar 

  9. Ivins, K. J., Bui, E. T., and Cotman, C. W. 1998. Beta-amyloid induces local neurite degeneration in cultured hippocampal neurons: Evidence for neuritic apoptosis. Neurobiol. Dis. 5:365–378.

    PubMed  Google Scholar 

  10. Ivins, K. J., Thornton, P. L., Rohn, T. T., and Cotman, C. W. 1999. Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8. Neurobiol. Dis. 6:440–449.

    PubMed  Google Scholar 

  11. Raoul, C., Henderson, C. E., and Pettmann, B. 1999. Programmed cell death of embryonic motorneurons triggered through the Fas death receptor. J. Cell. Biol. 147:1049–1062.

    PubMed  Google Scholar 

  12. Ashkenazi, A. and Dixit, V. M. 1999. Apoptosis control by death and decoy receptors. Curr. Opin. Cell Biol. 11:255–260.

    PubMed  Google Scholar 

  13. Colussi, P. A. and Kumar, S. 1999. Targeted disruption of caspase genes in mice: What they tell us about the functions of individual caspases in apoptosis. Immunol. Cell Biol. 77:58–63.

    PubMed  Google Scholar 

  14. Baker, S. J. and Reddy, E. P. 1998. Modulation of life and death by the TNF receptor superfamily. Oncogene. 17:3261–3270.

    PubMed  Google Scholar 

  15. Magnusson, C. and Vaux, D. L. 1999. Signalling by CD95 and TNF receptors: Not only life and death. Immunol. Cell Biol. 77:41–46.

    PubMed  Google Scholar 

  16. Scaffidi, C., Schmitz, I., Krammer, P. H., and Peter, M. E. 1999. The role of c-FLIP in modulation of CD95–induced apoptosis. J. Biol. Chem. 274:1541–1548.

    PubMed  Google Scholar 

  17. Tschopp, J., Irmler, M., and Thome, M. 1998. Inhibition of fas death signals by FLIPs. Curr. Opin. Immunol. 10:552–558.

    PubMed  Google Scholar 

  18. Thornberry, N. A. and Lazebnik, Y. 1998. Caspases: enemies within. Science 281:1312–1316.

    PubMed  Google Scholar 

  19. Darmon, A. J., Ley, T. J., Nicholson, D. W., and Bleackley, R. C. 1996. Cleavage of CPP32 by granzyme B represents a critical role for granzyme B in the induction of target cell DNA fragmentation. J. Biol. Chem. 271:21709–21712.

    PubMed  Google Scholar 

  20. Datta, R., Banach, D., Kojima, H., Talanian, R. V., Alnemri, E. S., Wong, W. W., and Kufe, D. W. 1996. Activation of the cpp32 protease in apoptosis induced by 1–beta-d-arabinofuranosylcytosine and other DNA-damaging agents. Blood 88:1936–1943.

    PubMed  Google Scholar 

  21. Nicholson, D. W., Ali, A., Thornberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallan, M., Gareau, Y., Griffin, P. R., Labelle, M., Lazebnik, Y. A., Munday, N. A., Raja, S. M., Smulson, M. E., Yamin, T.-T., Yu, V. L., and Miller, D. K. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis [see comments]. Nature 376:37–43.

    PubMed  Google Scholar 

  22. Thornberry, N. A. 1998. Caspases: Key mediators of apoptosis. Chem. Biol. 5:R97–R103.

    PubMed  Google Scholar 

  23. Mehmet, H. 2000. Caspases find a new place to hide. Nature 403:29–30.

    PubMed  Google Scholar 

  24. Canu, N., Dus, L., Barbato, C., Ciotti, M. T., Brancolini, C., Rinaldi, A. M., Novak, M., Cattaneo, A., Bradbury, A., and Calissano, P. 1998. Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. J. Neurosci. 18:7061–7074.

    PubMed  Google Scholar 

  25. Cohen, G. M. 1997. Caspases: The executioners of apoptosis. Biochem. J. 326:1–16.

    PubMed  Google Scholar 

  26. Gervais, F. G., Xu, D., Robertson, G. S., Vaillancourt, J. P., Zhu, Y., Huang, J., LeBlanc, A., Smith, D., Rigby, M., Shearman, M. S., Clarke, E. E., Zheng, H., Van Der Ploeg, L. H., Ruffolo, S. C., Thornberry, N. A., Xanthoudakis, S., Zamboni, R. J., Roy, S., and Nicholson, D. W. 1999. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic Abeta peptide formation. Cell 97:395–406.

    PubMed  Google Scholar 

  27. Lu, D. C., Rabizadeh, S., Chandra, S., Shayya, R. F., Ellerby, L. M., Ye, X., Salvesen, G. S., Koo, E. H., and Bredesen, D. E. 2000. A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor [see comments]. Nat. Med. 6:397–404.

    PubMed  Google Scholar 

  28. LeBlanc, A., Liu, H., Goodyer, C., Bergeron, C., and Hammond, J. 1999. Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease. J. Biol. Chem. 274:23426–23436.

    PubMed  Google Scholar 

  29. Su, J. H., Nichol, K. E., Sitch, T., Sheu, P., Chubb, C., Miller, B. L., Tomaselli, K. J., Kim, R. C., and Cotman, C. W. 2000. DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia. Exp. Neurol. 163:9–19.

    PubMed  Google Scholar 

  30. Braak, H. and Braak, E. 1991. Neuropathological stageing of Alzheimer-related changes. Acta Neuropath. 82:239–259.

    PubMed  Google Scholar 

  31. Srinivasan, A., Roth, K. A., Sayers, R. O., Shindler, K. S., Wong, A. M., Fritez, L. C., and Tomaselli, K. J. 1998. In Situ immunodetection of activated caspase-3 in apoptotic neurons in the developing nervous system. Cell Death Differentiation 5:1004–1016.

    Google Scholar 

  32. Biernat, J., Mandelkow, E.-M., Schroter, C., Lichtenberg-Kraag, B., Steiner, B., Berling, B., Meyer, H., Merchen, M., Vandermeeren, A., Goedert, M., and Mandelkow, E. 1992. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motif upstream of the microtubule binding region. EMBO J. 11:1593–1597.

    PubMed  Google Scholar 

  33. Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., and Lee, V. M.-Y. 1993. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10:1089–1099.

    PubMed  Google Scholar 

  34. Cummings, B. J., Mason, A. J., Kim, R. C., Sheu, P. C., and Anderson, A. J. 2002. Optimization of techniques for the maximal detection and quantification of Alzheimer's-related neuropathology with digital imaging. Neurobiol. Aging 23:161–170.

    PubMed  Google Scholar 

  35. Botchkina, G. I., Meistrell, M. E., 3rd, Botchkina, I. L., and Tracey, K. J. 1997. Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia. Mol. Med. 3:765–781.

    PubMed  Google Scholar 

  36. Hopkins, S. J. and Rothwell, N. J. 1995. Cytokines and the nervous system. I. Expression and recognition [see comments]. Trends Neurosci. 18:83–88.

    PubMed  Google Scholar 

  37. Bruunsgaard, H., Andersen-Ranberg, K., Jeune, B., Pedersen, A. N., Skinhoj, P., and Pedersen, B. K. 1999. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J. Gerontol. A. Biol. Sci. Med. Sci. 54:M357–M364.

    PubMed  Google Scholar 

  38. Tarkowski, E., Blennow, K., Wallin, A., and Tarkowski, A. 1999. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J. Clin. Immunol. 19:223–230.

    PubMed  Google Scholar 

  39. Maes, M., DeVos, N., Wauters, A., Demedts, P., Maurits, V. W., Neels, H., Bosmans, E., Altamura, C., Lin, A., Song, C., Vandenbroucke, M., and Scharpe, S. 1999. Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease. J. Psychiatr. Res. 33:397–405.

    PubMed  Google Scholar 

  40. Aggarwal, S., Gollapudi, S., and Gupta, S. 1999. Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. J. Immunol. 162:2154–2161.

    PubMed  Google Scholar 

  41. Venters, H. D., Tang, Q., Liu, Q., VanHoy, R. W., Dantzer, R., and Kelley, K. W. 1999. A new mechanism of neurodegenera-tion: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. USA 96:9879–9884.

    PubMed  Google Scholar 

  42. Ashkenazi, A. and Dixit, V. M. 1998. Death receptors: signaling and modulation. Science 281:1305–1308.

    PubMed  Google Scholar 

  43. Baker, S. J. and Reddy, E. P. 1996. Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12:1–9.

    PubMed  Google Scholar 

  44. Chao, C. C. and Hu, S. 1994. Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev. Neurosci. 16:172–179.

    PubMed  Google Scholar 

  45. Louis, J. C., Magal, E., Takayama, S., and Varon, S. 1993. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689–692.

    PubMed  Google Scholar 

  46. Barger, S. W., Horster, D., Furukawa, K., Goodman, Y., Krieglstein, J., and Mattson, M. P. 1995. Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc. Natl. Acad. Sci. USA 92:9328–9332.

    PubMed  Google Scholar 

  47. Cheng, B., Christakos, S., and Mattson, M. P. 1994. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12:139–153.

    PubMed  Google Scholar 

  48. Hsu, H., Shu, H. B., Pan, M. G., and Goeddel, D. V. 1996. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84: 299–308.

    PubMed  Google Scholar 

  49. Jiang, Y., Woronicz, J. D., Liu, W., and Goeddel, D. V. 1999. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science 283:543–546.

    PubMed  Google Scholar 

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  1. Institute for Brain Aging and Dementia, University of California Irvine, Irvine, California

    Ming Zhao, David H. Cribbs, Aileen J. Anderson, Brian J. Cummings, Joseph H. Su, Andrea J. Wasserman & Carl W. Cotman

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  1. Ming Zhao
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Correspondence to Carl W. Cotman.

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Zhao, M., Cribbs, D.H., Anderson, A.J. et al. The Induction of the TNFα Death Domain Signaling Pathway in Alzheimer's Disease Brain. Neurochem Res 28, 307–318 (2003). https://doi.org/10.1023/A:1022337519035

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