Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Oct 1;98(7):1626–1632. doi: 10.1172/JCI118957

Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice.

F M LaFerla 1, C K Hall 1, L Ngo 1, G Jay 1
PMCID: PMC507596  PMID: 8833912

Abstract

The finding that intracellular expression of the beta-amyloid protein (Abeta) under a neuron-specific promoter led progressively to degeneration and death of neurons in the brains of transgenic mice provides a unique opportunity to utilize this animal model to both understand the mechanism that underlies neuronal cell death and define the complexity of events which may ensue. We observed a correlation between Abeta accumulation in selective neurons and activation of p53, a protein that has been implicated in the induction of apoptosis. Histological and immunohistochemical evaluations of adjacent brain sections suggest that expression of p53 is accompanied by nuclear DNA fragmentation. In certain regions with marked neuronal cell death, extracellular deposition of A(beta) became evident, together with the local activation of astrocytes. Interestingly, the neuritic structures underlying the Abeta deposits showed altered synaptophysin immunoreactivity and morphologic evidence for damage. This transgenic mouse model suggests that intracellular generation of the Abeta protein not only leads to the death of the neuron but may also functionally impair neighboring neurons as well. It further offers a mechanism whereby neuritic plaques may be derived.

Full Text

The Full Text of this article is available as a PDF (484.7 KB).

Selected References

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

  1. Behl C., Davis J. B., Lesley R., Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994 Jun 17;77(6):817–827. doi: 10.1016/0092-8674(94)90131-7. [DOI] [PubMed] [Google Scholar]
  2. Busciglio J., Gabuzda D. H., Matsudaira P., Yankner B. A. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2092–2096. doi: 10.1073/pnas.90.5.2092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cai X. D., Golde T. E., Younkin S. G. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514–516. doi: 10.1126/science.8424174. [DOI] [PubMed] [Google Scholar]
  4. Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A. Y., Seubert P., Vigo-Pelfrey C., Lieberburg I., Selkoe D. J. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672–674. doi: 10.1038/360672a0. [DOI] [PubMed] [Google Scholar]
  5. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  6. Fukuchi K., Kamino K., Deeb S. S., Smith A. C., Dang T., Martin G. M. Overexpression of amyloid precursor protein alters its normal processing and is associated with neurotoxicity. Biochem Biophys Res Commun. 1992 Jan 15;182(1):165–173. doi: 10.1016/s0006-291x(05)80126-3. [DOI] [PubMed] [Google Scholar]
  7. Games D., Adams D., Alessandrini R., Barbour R., Berthelette P., Blackwell C., Carr T., Clemens J., Donaldson T., Gillespie F. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995 Feb 9;373(6514):523–527. doi: 10.1038/373523a0. [DOI] [PubMed] [Google Scholar]
  8. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Guntern R., Bouras C., Hof P. R., Vallet P. G. An improved thioflavine S method for staining neurofibrillary tangles and senile plaques in Alzheimer's disease. Experientia. 1992 Jan 15;48(1):8–10. doi: 10.1007/BF01923594. [DOI] [PubMed] [Google Scholar]
  10. Haass C., Schlossmacher M. G., Hung A. Y., Vigo-Pelfrey C., Mellon A., Ostaszewski B. L., Lieberburg I., Koo E. H., Schenk D., Teplow D. B. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992 Sep 24;359(6393):322–325. doi: 10.1038/359322a0. [DOI] [PubMed] [Google Scholar]
  11. Hensley K., Carney J. M., Mattson M. P., Aksenova M., Harris M., Wu J. F., Floyd R. A., Butterfield D. A. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3270–3274. doi: 10.1073/pnas.91.8.3270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hockenbery D. Defining apoptosis. Am J Pathol. 1995 Jan;146(1):16–19. [PMC free article] [PubMed] [Google Scholar]
  13. Korsmeyer S. J. Regulators of cell death. Trends Genet. 1995 Mar;11(3):101–105. doi: 10.1016/S0168-9525(00)89010-1. [DOI] [PubMed] [Google Scholar]
  14. LaFerla F. M., Tinkle B. T., Bieberich C. J., Haudenschild C. C., Jay G. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet. 1995 Jan;9(1):21–30. doi: 10.1038/ng0195-21. [DOI] [PubMed] [Google Scholar]
  15. Li Y., Chopp M., Zhang Z. G., Zaloga C., Niewenhuis L., Gautam S. p53-immunoreactive protein and p53 mRNA expression after transient middle cerebral artery occlusion in rats. Stroke. 1994 Apr;25(4):849–856. doi: 10.1161/01.str.25.4.849. [DOI] [PubMed] [Google Scholar]
  16. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  17. Majno G., Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995 Jan;146(1):3–15. [PMC free article] [PubMed] [Google Scholar]
  18. Martin B. L., Schrader-Fischer G., Busciglio J., Duke M., Paganetti P., Yankner B. A. Intracellular accumulation of beta-amyloid in cells expressing the Swedish mutant amyloid precursor protein. J Biol Chem. 1995 Nov 10;270(45):26727–26730. doi: 10.1074/jbc.270.45.26727. [DOI] [PubMed] [Google Scholar]
  19. Martin L. J., Pardo C. A., Cork L. C., Price D. L. Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol. 1994 Dec;145(6):1358–1381. [PMC free article] [PubMed] [Google Scholar]
  20. Masliah E., Terry R. D., Alford M., DeTeresa R., Hansen L. A. Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer's disease. Am J Pathol. 1991 Jan;138(1):235–246. [PMC free article] [PubMed] [Google Scholar]
  21. Murphy G. M., Jr, Forno L. S., Higgins L., Scardina J. M., Eng L. F., Cordell B. Development of a monoclonal antibody specific for the COOH-terminal of beta-amyloid 1-42 and its immunohistochemical reactivity in Alzheimer's disease and related disorders. Am J Pathol. 1994 May;144(5):1082–1088. [PMC free article] [PubMed] [Google Scholar]
  22. Oren M. Relationship of p53 to the control of apoptotic cell death. Semin Cancer Biol. 1994 Jun;5(3):221–227. [PubMed] [Google Scholar]
  23. Perry G., Cras P., Siedlak S. L., Tabaton M., Kawai M. Beta protein immunoreactivity is found in the majority of neurofibrillary tangles of Alzheimer's disease. Am J Pathol. 1992 Feb;140(2):283–290. [PMC free article] [PubMed] [Google Scholar]
  24. Price D. L., Sisodia S. S. Cellular and molecular biology of Alzheimer's disease and animal models. Annu Rev Med. 1994;45:435–446. doi: 10.1146/annurev.med.45.1.435. [DOI] [PubMed] [Google Scholar]
  25. Sakhi S., Bruce A., Sun N., Tocco G., Baudry M., Schreiber S. S. p53 induction is associated with neuronal damage in the central nervous system. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7525–7529. doi: 10.1073/pnas.91.16.7525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sasahara M., Fries J. W., Raines E. W., Gown A. M., Westrum L. E., Frosch M. P., Bonthron D. T., Ross R., Collins T. PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell. 1991 Jan 11;64(1):217–227. doi: 10.1016/0092-8674(91)90223-l. [DOI] [PubMed] [Google Scholar]
  27. Selkoe D. J. Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci. 1994;17:489–517. doi: 10.1146/annurev.ne.17.030194.002421. [DOI] [PubMed] [Google Scholar]
  28. Shearman M. S., Ragan C. I., Iversen L. L. Inhibition of PC12 cell redox activity is a specific, early indicator of the mechanism of beta-amyloid-mediated cell death. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1470–1474. doi: 10.1073/pnas.91.4.1470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shoji M., Golde T. E., Ghiso J., Cheung T. T., Estus S., Shaffer L. M., Cai X. D., McKay D. M., Tintner R., Frangione B. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992 Oct 2;258(5079):126–129. doi: 10.1126/science.1439760. [DOI] [PubMed] [Google Scholar]
  30. Tishler R. B., Calderwood S. K., Coleman C. N., Price B. D. Increases in sequence specific DNA binding by p53 following treatment with chemotherapeutic and DNA damaging agents. Cancer Res. 1993 May 15;53(10 Suppl):2212–2216. [PubMed] [Google Scholar]
  31. Ueda H., Ullrich S. J., Gangemi J. D., Kappel C. A., Ngo L., Feitelson M. A., Jay G. Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet. 1995 Jan;9(1):41–47. doi: 10.1038/ng0195-41. [DOI] [PubMed] [Google Scholar]
  32. Wertkin A. M., Turner R. S., Pleasure S. J., Golde T. E., Younkin S. G., Trojanowski J. Q., Lee V. M. Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9513–9517. doi: 10.1073/pnas.90.20.9513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yang A. J., Knauer M., Burdick D. A., Glabe C. Intracellular A beta 1-42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells. J Biol Chem. 1995 Jun 16;270(24):14786–14792. doi: 10.1074/jbc.270.24.14786. [DOI] [PubMed] [Google Scholar]
  34. Yoshikawa K., Aizawa T., Hayashi Y. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature. 1992 Sep 3;359(6390):64–67. doi: 10.1038/359064a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES