Mechanism of amyloid β protein induced neuronal cell death: current concepts and future perspectives

  • C. Behl
  • Y. Sagara
Conference paper


Amyloid β protein (A β) is a 40 to 43 amino acid peptide which is associated with plaques in the brains of Alzheimer’s patients and is cytotoxic to cultured neurons. A number of antioxidants protect both primary central nervous system (CNS) cultures and clonal cell lines from Aβ toxicity, suggesting that one pathway to Aβ cytotoxicity results in free radical damage. Aβ causes increased levels of H2O2 and lipid peroxides to accumulate in cells. The H2O2 degrading enzyme catalase protects cells from Aβ toxicity. Clonal cell lines selected for their resistance to Aβ toxicity also become resistant to the cytolytic action of H2O2. In addition, Aβ induces NF-kB activity, a transcription factor thought to be regulated by oxidative stress. Finally, Aβ induced H2O2 production and Aβ toxicity are blocked by reagents which inhibit flavin oxidases, suggesting that Aβ activates a member of this class of enzymes. These results show that the cytotoxic action of Aβ on neurons results from free radical damage to susceptible cells (Behl et al., 1994b).


PC12 Cell Neuronal Cell Death Free Radical Damage Clonal Cell Line Amyloid Beta Protein 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sei USA 90: 7915–7922CrossRefGoogle Scholar
  2. Behl C, Davis J, Cole GM, Schubert D (1992) Vitamin E protects nerve cells from amyloid β protein toxicity. Biochem Biophys Res Com 186: 944–952PubMedCrossRefGoogle Scholar
  3. Behl C, Davis JB, Klier FG, Schubert D (1994a) Amyloid β protein induces necrosis rather than apoptosis. Brain Res 645: 253–264PubMedCrossRefGoogle Scholar
  4. Behl C, Davis JB, Lesley R, Schubert D (1994b) Hydrogen peroxide mediates amyloid β protein toxicity. Cell 77: 817–827PubMedCrossRefGoogle Scholar
  5. Behl C, Lezoualc’h F, Trapp T, Widmann M, Skutella T, Holsboer F (1995) Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology 138: 101–106CrossRefGoogle Scholar
  6. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262: 689–695PubMedCrossRefGoogle Scholar
  7. Cross AR (1990) Inhibitors of leukocyte superoxide generating oxidase. Free Rad Biol Med 8: 71–93PubMedCrossRefGoogle Scholar
  8. Cross AR, Jones OTG (1991) Enzymatic mechanisms of superoxide production. Biochem Biophys Acta 1057: 281–298PubMedCrossRefGoogle Scholar
  9. Glenner GG (1988) Alzheimer’s disease: its proteins and genes. Cell 52: 307–308PubMedCrossRefGoogle Scholar
  10. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73: 2424–2428PubMedCrossRefGoogle Scholar
  11. Halliwell B, Gutteridge JMC (1989) Free radicals in biology and medicine. Oxford University Press, Oxford, pp 188–266Google Scholar
  12. Hedley D, Chow S (1992) Fluorocytometric measurement of lipid peroxidation in vital cells using parinaric acid. Cytometry 13: 686–692PubMedCrossRefGoogle Scholar
  13. Keston AS, Brandt R (1965) The fluorometric analysis of ultramicro quantities of hydrogen peroxide. Anal Biochem 11: 1–5PubMedCrossRefGoogle Scholar
  14. Koh J, Yang LL, Cotman CW (1990) β amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 533: 315–320PubMedCrossRefGoogle Scholar
  15. Kojima S, Nomura T, Icho T, Kajiwara Y, Kitabatake K, Kubota K (1993) Inhibitory effect of neopterin on NADPH-dependent superoxide-generating oxidase of rat peritoneal macrophages. FEBS Lett 329: 125–128PubMedCrossRefGoogle Scholar
  16. Olanow CW (1993) A radical hypothesis for neurodegeneration. TINS 16: 439–444PubMedGoogle Scholar
  17. Reul JMHM, deKloet ER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential accupation. Endocrinology 117: 2505–2511PubMedCrossRefGoogle Scholar
  18. Royall JA, Ischiropoulos H (1993) Evaluation of 2′,7′ dichlorofluorescin and dihydrorhodamine 123 as fluorescent probes for intracellular H2O2 in cultured endothelial cells. Arch Biochem Biophys 302: 348–355PubMedCrossRefGoogle Scholar
  19. Sagara Y, Behl C, Dargusch R, Klier G, Schubert D (1995a) Increased antioxidant enzyme activity in amyloid protein resistant PC12 cells. J Neurosci 16: 497–505Google Scholar
  20. Sapolsky R, Packan D, Vale W (1988) Glucocorticoid toxicity in the hippocampus: in vitro demonstration. Brain Res 453: 367–370PubMedCrossRefGoogle Scholar
  21. Schubert D (1984) Developmental biology of cultured nerve, muscle, and glia. Wiley & Sons, New YorkGoogle Scholar
  22. Schubert D (1994) The structure and function of Alzheimer’s amyloid beta proteins. R.G. Landes Company, AustinGoogle Scholar
  23. Schubert D, Heinemann S, Carlisle W, Tarikas H, Kimes B, Steinbach JH, Culp W, Brandt BL (1974) Clonal cell lines from the rat central nervous system. Nature 249: 224–227PubMedCrossRefGoogle Scholar
  24. Schubert D, Kimura H, Maher P (1992) Growth factors and vitamin E modify neuronal glutamate toxicity. Proc Natl Acad Sci USA 89: 8264–8268PubMedCrossRefGoogle Scholar
  25. Schubert D, Behl C, Lesley R, Brack A, Dargusch R, Sagara Y, Kimura H (1995) Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad Sci USA 92: 1989–1993PubMedCrossRefGoogle Scholar
  26. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid β protein: reversal by tachykinin neuropeptides. Science 25: 279–282CrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1997

Authors and Affiliations

  • C. Behl
    • 1
  • Y. Sagara
    • 2
  1. 1.Clinical InstituteMax-Planck-Institute of PsychiatryMunichGermany
  2. 2.The Salk Institute for Biological StudiesSan DiegoUSA

Personalised recommendations