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. 1996 May 14;93(10):5146–5150. doi: 10.1073/pnas.93.10.5146

Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture.

R P Parshad 1, K K Sanford 1, F M Price 1, L K Melnick 1, L E Nee 1, M B Schapiro 1, R E Tarone 1, J H Robbins 1
PMCID: PMC39422  PMID: 8643543

Abstract

The neurodegeneration and amyloid deposition of sporadic Alzheimer disease (AD) also occur in familial AD and in all trisomy-21 Down syndrome (DS) patients, suggesting a common pathogenetic mechanism. We investigated whether defective processing of damaged DNA might be that mechanism, as postulated for the neurodegeneration in xeroderma pigmentosum, a disease with defective repair not only of UV radiation-induced, but also of some oxygen free radical-induced, DNA lesions. We irradiated AD and DS skin fibroblasts or blood lymphocytes with fluorescent light, which is known to cause free radical-induced DNA damage. The cells were then treated with either beta-cytosine arabinoside (araC) or caffeine, and chromatid breaks were quantified. At least 28 of 31 normal donors and 10 of 11 donors with nonamyloid neurodegenerations gave normal test results. All 12 DS, 11 sporadic AD, and 16 familial AD patients tested had abnormal araC and caffeine tests, as did XP-A cells. In one of our four AD families, an abnormal caffeine test was found in all 10 afflicted individuals (including 3 asymptomatic when their skin biopsies were obtained) and in 8 of 11 offspring at a 50% risk for AD. Our tests could prove useful in predicting inheritance of familial AD and in supporting, or rendering unlikely, the diagnosis of sporadic AD in patients suspected of having the disease.

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Selected References

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

  1. Athas W. F., Hedayati M. A., Matanoski G. M., Farmer E. R., Grossman L. Development and field-test validation of an assay for DNA repair in circulating human lymphocytes. Cancer Res. 1991 Nov 1;51(21):5786–5793. [PubMed] [Google Scholar]
  2. Boerrigter M. E., Wei J. Y., Vijg J. DNA repair and Alzheimer's disease. J Gerontol. 1992 Nov;47(6):B177–B184. doi: 10.1093/geronj/47.6.b177. [DOI] [PubMed] [Google Scholar]
  3. Chen P., Kidson C., Lavin M. Heterogeneity in Alzheimer's disease: evidence from cellular radiosensitivity and complementation of this phenotype. Mutat Res. 1991 Jan;256(1):21–27. doi: 10.1016/0921-8734(91)90029-b. [DOI] [PubMed] [Google Scholar]
  4. Cleaver J. E., McDowell M., Jones C., Wood R., Karentz D. Mutation and expression of the XPA gene in revertants and hybrids of a xeroderma pigmentosum cell line. Somat Cell Mol Genet. 1994 Jul;20(4):327–337. doi: 10.1007/BF02254721. [DOI] [PubMed] [Google Scholar]
  5. Eveno E., Bourre F., Quilliet X., Chevallier-Lagente O., Roza L., Eker A. P., Kleijer W. J., Nikaido O., Stefanini M., Hoeijmakers J. H. Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases. Cancer Res. 1995 Oct 1;55(19):4325–4332. [PubMed] [Google Scholar]
  6. Fram R. J., Kufe D. W. Inhibition of DNA excision repair and the repair of X-ray-induced DNA damage by cytosine arabinoside and hydroxyurea. Pharmacol Ther. 1985;31(3):165–176. doi: 10.1016/0163-7258(85)90021-x. [DOI] [PubMed] [Google Scholar]
  7. Grossman L., Thiagalingam S. Nucleotide excision repair, a tracking mechanism in search of damage. J Biol Chem. 1993 Aug 15;268(23):16871–16874. [PubMed] [Google Scholar]
  8. Hanawalt P. C. Transcription-coupled repair and human disease. Science. 1994 Dec 23;266(5193):1957–1958. doi: 10.1126/science.7801121. [DOI] [PubMed] [Google Scholar]
  9. Leadon S. A., Cooper P. K. Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10499–10503. doi: 10.1073/pnas.90.22.10499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Link C. J., Jr, Robbins J. H., Bohr V. A. Gene specific DNA repair of damage induced in familial Alzheimer disease cells by ultraviolet irradiation or by nitrogen mustard. Mutat Res. 1995 Mar;336(2):115–121. doi: 10.1016/0921-8777(94)00051-7. [DOI] [PubMed] [Google Scholar]
  11. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
  12. Moshell A. N., Tarone R. E., Newfield S. A., Andrews A. D., Robbins J. H. A simple and rapid method for evaluating the survival of xeroderma pigmentosum lymphoid lines after irradiation with ultraviolet light. In Vitro. 1981 Apr;17(4):299–307. doi: 10.1007/BF02618141. [DOI] [PubMed] [Google Scholar]
  13. Otsuka F., Tarone R. E., Seguin L. R., Robbins J. H. Hypersensitivity to ionizing radiation in cultured cells from Down syndrome patients. J Neurol Sci. 1985 May-Jun;69(1-2):103–112. doi: 10.1016/0022-510x(85)90011-5. [DOI] [PubMed] [Google Scholar]
  14. Parshad R., Sanford K. K., Jones G. M. Chromatid damage induced by fluorescent light during G2 phase in normal and Gardner syndrome fibroblasts. Interpretation in terms of deficient DNA repair. Mutat Res. 1985 Aug;151(1):57–63. doi: 10.1016/0027-5107(85)90182-4. [DOI] [PubMed] [Google Scholar]
  15. Parshad R., Tarone R. E., Price F. M., Sanford K. K. Cytogenetic evidence for differences in DNA incision activity in xeroderma pigmentosum group A, C and D cells after X-irradiation during G2 phase. Mutat Res. 1993 Aug;294(2):149–155. doi: 10.1016/0921-8777(93)90023-a. [DOI] [PubMed] [Google Scholar]
  16. Price F. M., Parshad R., Tarone R. E., Sanford K. K. Radiation-induced chromatid aberrations in Cockayne syndrome and xeroderma pigmentosum group C fibroblasts in relation to cancer predisposition. Cancer Genet Cytogenet. 1991 Nov;57(1):1–10. doi: 10.1016/0165-4608(91)90183-u. [DOI] [PubMed] [Google Scholar]
  17. Robbins J. H. A childhood neurodegeneration due to defective DNA repair: a novel concept of disease based on studies xeroderma pigmentosum. J Child Neurol. 1989 Apr;4(2):143–146. doi: 10.1177/088307388900400215. [DOI] [PubMed] [Google Scholar]
  18. Robbins J. H., Brumback R. A., Mendiones M., Barrett S. F., Carl J. R., Cho S., Denckla M. B., Ganges M. B., Gerber L. H., Guthrie R. A. Neurological disease in xeroderma pigmentosum. Documentation of a late onset type of the juvenile onset form. Brain. 1991 Jun;114(Pt 3):1335–1361. doi: 10.1093/brain/114.3.1335. [DOI] [PubMed] [Google Scholar]
  19. Robbins J. H., Otsuka F., Tarone R. E., Polinsky R. J., Brumback R. A., Nee L. E. Parkinson's disease and Alzheimer's disease: hypersensitivity to X rays in cultured cell lines. J Neurol Neurosurg Psychiatry. 1985 Sep;48(9):916–923. doi: 10.1136/jnnp.48.9.916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Robison S. H., Munzer J. S., Tandan R., Bradley W. G. Alzheimer's disease cells exhibit defective repair of alkylating agent-induced DNA damage. Ann Neurol. 1987 Mar;21(3):250–258. doi: 10.1002/ana.410210306. [DOI] [PubMed] [Google Scholar]
  21. Rünger T. M., Epe B., Möller K. Repair of ultraviolet B and singlet oxygen-induced DNA damage in xeroderma pigmentosum cells. J Invest Dermatol. 1995 Jan;104(1):68–73. doi: 10.1111/1523-1747.ep12613504. [DOI] [PubMed] [Google Scholar]
  22. Sanford K. K., Parshad R., Gantt R., Tarone R. E., Jones G. M., Price F. M. Factors affecting and significance of G2 chromatin radiosensitivity in predisposition to cancer. Int J Radiat Biol. 1989 Jun;55(6):963–981. doi: 10.1080/09553008914551001. [DOI] [PubMed] [Google Scholar]
  23. Sanford K. K., Parshad R., Price F. M., Jones G. M., Tarone R. E., Eierman L., Hale P., Waldmann T. A. Enhanced chromatid damage in blood lymphocytes after G2 phase x irradiation, a marker of the ataxia-telangiectasia gene. J Natl Cancer Inst. 1990 Jun 20;82(12):1050–1054. doi: 10.1093/jnci/82.12.1050. [DOI] [PubMed] [Google Scholar]
  24. Sanford K. K., Parshad R., Price F. M., Tarone R. E., Schapiro M. B. X-ray-induced chromatid damage in cells from Down syndrome and Alzheimer disease patients in relation to DNA repair and cancer proneness. Cancer Genet Cytogenet. 1993 Oct 1;70(1):25–30. doi: 10.1016/0165-4608(93)90127-8. [DOI] [PubMed] [Google Scholar]
  25. Satoh M. S., Jones C. J., Wood R. D., Lindahl T. DNA excision-repair defect of xeroderma pigmentosum prevents removal of a class of oxygen free radical-induced base lesions. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6335–6339. doi: 10.1073/pnas.90.13.6335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754–760. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]
  27. Tobi S. E., Moquet J. E., Edwards A. A., Lloyd D. C., Itzhaki R. F. Chromosomal radiosensitivity of lymphocytes from Alzheimer's disease patients. J Med Genet. 1990 Jul;27(7):437–440. doi: 10.1136/jmg.27.7.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wei Q., Matanoski G. M., Farmer E. R., Hedayati M. A., Grossman L. DNA repair and aging in basal cell carcinoma: a molecular epidemiology study. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1614–1618. doi: 10.1073/pnas.90.4.1614. [DOI] [PMC free article] [PubMed] [Google Scholar]

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