Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1995 Nov;147(5):1465–1476.

Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5.

J P Brion 1, A M Couck 1
PMCID: PMC1869502  PMID: 7485409

Abstract

The immunoreactivity of cortical and brainstem-type Lewy bodies has been investigates with antibodies to the cyclin-dependent kinase 5 (cdk5), to the extracellular regulated kinase 1 (ERK-1), and to the cdc2p34 kinase and with antibodies specific for phosphorylation epitopes typical of paired helical filament-tau (PHF-tau). Both cortical and brainstem-type Lewy bodies in diffuse Lewy body disease and brainstem-type Lewy bodies in Parkinson's disease were found to be immunoreactive for cdk5 but not for cdc2p34 or ERK-1 or with the PHF-tau antibodies. Double immunolabeling showed that cdk5-positive Lewy bodies were also ubiquitin immunoreactive and that cdk5 antibodies labeled as many Lewy bodies as ubiquitin antibodies in adequately fixed tissue. The cdk5 immunoreactivity of Lewy bodies was abolished by preabsorption of the antibody with a cdk5 peptide. The antibodies to cdk5 labeled a single 33-kd species on Western blots of human brain homogenates, with a similar intensity in control, diffuse Lewy body disease, and Alzheimer's disease, and this cdk5 species was found mainly in the particulate fraction of brain homogenates. This observation suggests that cdk5 might be a protein kinase involved in the phosphorylation of a molecular component of Lewy bodies, for example, neurofilament proteins known to be present in these inclusions.

Full text

PDF
1465

Images in this article

1467Figure 1
on p.1467
1469Figure 2
on p.1469
1470Figure 3
on p.1470
1471Figure 4
on p.1471
1472Figure 5
on p.1472

Selected References

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

  1. Baumann K., Mandelkow E. M., Biernat J., Piwnica-Worms H., Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 1993 Dec 28;336(3):417–424. doi: 10.1016/0014-5793(93)80849-p. [DOI] [PubMed] [Google Scholar]
  2. Braak H., Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar]
  3. Brion J. P., Couck A. M., Robertson J., Loviny T. L., Anderton B. H. Neurofilament monoclonal antibodies RT97 and 8D8 recognize different modified epitopes in paired helical filament-tau in Alzheimer's disease. J Neurochem. 1993 Apr;60(4):1372–1382. doi: 10.1111/j.1471-4159.1993.tb03298.x. [DOI] [PubMed] [Google Scholar]
  4. Brion J. P., Guilleminot J., Couchie D., Flament-Durand J., Nunez J. Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing and adult rat cerebellum. Neuroscience. 1988 Apr;25(1):139–146. doi: 10.1016/0306-4522(88)90013-9. [DOI] [PubMed] [Google Scholar]
  5. Brion J. P., Octave J. N., Couck A. M. Distribution of the phosphorylated microtubule-associated protein tau in developing cortical neurons. Neuroscience. 1994 Dec;63(3):895–909. doi: 10.1016/0306-4522(94)90533-9. [DOI] [PubMed] [Google Scholar]
  6. Dale G. E., Probst A., Luthert P., Martin J., Anderton B. H., Leigh P. N. Relationships between Lewy bodies and pale bodies in Parkinson's disease. Acta Neuropathol. 1992;83(5):525–529. doi: 10.1007/BF00310030. [DOI] [PubMed] [Google Scholar]
  7. Dickson D. W., Davies P., Mayeux R., Crystal H., Horoupian D. S., Thompson A., Goldman J. E. Diffuse Lewy body disease. Neuropathological and biochemical studies of six patients. Acta Neuropathol. 1987;75(1):8–15. doi: 10.1007/BF00686786. [DOI] [PubMed] [Google Scholar]
  8. Dickson D. W., Schmidt M. L., Lee V. M., Zhao M. L., Yen S. H., Trojanowski J. Q. Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathol. 1994;87(3):269–276. doi: 10.1007/BF00296742. [DOI] [PubMed] [Google Scholar]
  9. Forno L. S., Sternberger L. A., Sternberger N. H., Strefling A. M., Swanson K., Eng L. F. Reaction of Lewy bodies with antibodies to phosphorylated and non-phosphorylated neurofilaments. Neurosci Lett. 1986 Mar 14;64(3):253–258. doi: 10.1016/0304-3940(86)90337-x. [DOI] [PubMed] [Google Scholar]
  10. Galloway P. G., Bergeron C., Perry G. The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from those of idiopathic Parkinson disease. Neurosci Lett. 1989 May 22;100(1-3):6–10. doi: 10.1016/0304-3940(89)90651-4. [DOI] [PubMed] [Google Scholar]
  11. Galloway P. G., Grundke-Iqbal I., Iqbal K., Perry G. Lewy bodies contain epitopes both shared and distinct from Alzheimer neurofibrillary tangles. J Neuropathol Exp Neurol. 1988 Nov;47(6):654–663. doi: 10.1097/00005072-198811000-00008. [DOI] [PubMed] [Google Scholar]
  12. Galloway P. G., Mulvihill P., Perry G. Filaments of Lewy bodies contain insoluble cytoskeletal elements. Am J Pathol. 1992 Apr;140(4):809–822. [PMC free article] [PubMed] [Google Scholar]
  13. Gibb W. R., Esiri M. M., Lees A. J. Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body dementia). Brain. 1987 Oct;110(Pt 5):1131–1153. doi: 10.1093/brain/110.5.1131. [DOI] [PubMed] [Google Scholar]
  14. Gibb W. R. Idiopathic Parkinson's disease and the Lewy body disorders. Neuropathol Appl Neurobiol. 1986 May-Jun;12(3):223–234. doi: 10.1111/j.1365-2990.1986.tb00136.x. [DOI] [PubMed] [Google Scholar]
  15. Goedert M., Cohen E. S., Jakes R., Cohen P. p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. FEBS Lett. 1992 Nov 2;312(1):95–99. doi: 10.1016/0014-5793(92)81418-l. [DOI] [PubMed] [Google Scholar]
  16. Goedert M., Jakes R., Crowther R. A., Cohen P., Vanmechelen E., Vandermeeren M., Cras P. Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: identification of phosphorylation sites in tau protein. Biochem J. 1994 Aug 1;301(Pt 3):871–877. doi: 10.1042/bj3010871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goedert M., Jakes R., Crowther R. A., Six J., Lübke U., Vandermeeren M., Cras P., Trojanowski J. Q., Lee V. M. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5066–5070. doi: 10.1073/pnas.90.11.5066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goldman J. E., Yen S. H., Chiu F. C., Peress N. S. Lewy bodies of Parkinson's disease contain neurofilament antigens. Science. 1983 Sep 9;221(4615):1082–1084. doi: 10.1126/science.6308771. [DOI] [PubMed] [Google Scholar]
  19. Hanger D. P., Hughes K., Woodgett J. R., Brion J. P., Anderton B. H. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett. 1992 Nov 23;147(1):58–62. doi: 10.1016/0304-3940(92)90774-2. [DOI] [PubMed] [Google Scholar]
  20. Hansen L., Salmon D., Galasko D., Masliah E., Katzman R., DeTeresa R., Thal L., Pay M. M., Hofstetter R., Klauber M. The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990 Jan;40(1):1–8. doi: 10.1212/wnl.40.1.1. [DOI] [PubMed] [Google Scholar]
  21. Harrington C. R., Perry R. H., Perry E. K., Hurt J., McKeith I. G., Roth M., Wischik C. M. Senile dementia of Lewy body type and Alzheimer type are biochemically distinct in terms of paired helical filaments and hyperphosphorylated tau protein. Dementia. 1994 Sep-Oct;5(5):215–228. doi: 10.1159/000106727. [DOI] [PubMed] [Google Scholar]
  22. Hellmich M. R., Pant H. C., Wada E., Battey J. F. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10867–10871. doi: 10.1073/pnas.89.22.10867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hill W. D., Lee V. M., Hurtig H. I., Murray J. M., Trojanowski J. Q. Epitopes located in spatially separate domains of each neurofilament subunit are present in Parkinson's disease Lewy bodies. J Comp Neurol. 1991 Jul 1;309(1):150–160. doi: 10.1002/cne.903090111. [DOI] [PubMed] [Google Scholar]
  24. Hyman B. T., Elvhage T. E., Reiter J. Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease. Am J Pathol. 1994 Mar;144(3):565–572. [PMC free article] [PubMed] [Google Scholar]
  25. Ino H., Mochizuki T., Yanaihara N., Chiba T. p34cdc2 homologue is located in nucleoli of the nervous and endocrine systems. Brain Res. 1993 Jun 18;614(1-2):131–136. doi: 10.1016/0006-8993(93)91026-o. [DOI] [PubMed] [Google Scholar]
  26. Iwatsubo T., Nakano I., Fukunaga K., Miyamoto E. Ca2+/calmodulin-dependent protein kinase II immunoreactivity in Lewy bodies. Acta Neuropathol. 1991;82(3):159–163. doi: 10.1007/BF00294440. [DOI] [PubMed] [Google Scholar]
  27. Kahn J., Anderton B. H., Gibb W. R., Lees A. J., Wells F. R., Marsden C. D. Neuronal filaments in Alzheimer's, Pick's, and Parkinson's diseases. N Engl J Med. 1985 Aug 22;313(8):520–521. doi: 10.1056/NEJM198508223130817. [DOI] [PubMed] [Google Scholar]
  28. Kobayashi S., Ishiguro K., Omori A., Takamatsu M., Arioka M., Imahori K., Uchida T. A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS Lett. 1993 Dec 6;335(2):171–175. doi: 10.1016/0014-5793(93)80723-8. [DOI] [PubMed] [Google Scholar]
  29. Ksiezak-Reding H., Dickson D. W., Davies P., Yen S. H. Recognition of tau epitopes by anti-neurofilament antibodies that bind to Alzheimer neurofibrillary tangles. Proc Natl Acad Sci U S A. 1987 May;84(10):3410–3414. doi: 10.1073/pnas.84.10.3410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kuzuhara S., Mori H., Izumiyama N., Yoshimura M., Ihara Y. Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. 1988;75(4):345–353. doi: 10.1007/BF00687787. [DOI] [PubMed] [Google Scholar]
  31. Ledesma M. D., Correas I., Avila J., Díaz-Nido J. Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer's disease. FEBS Lett. 1992 Aug 17;308(2):218–224. doi: 10.1016/0014-5793(92)81278-t. [DOI] [PubMed] [Google Scholar]
  32. Lee V. M., Otvos L., Jr, Schmidt M. L., Trojanowski J. Q. Alzheimer disease tangles share immunological similarities with multiphosphorylation repeats in the two large neurofilament proteins. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7384–7388. doi: 10.1073/pnas.85.19.7384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lew J., Beaudette K., Litwin C. M., Wang J. H. Purification and characterization of a novel proline-directed protein kinase from bovine brain. J Biol Chem. 1992 Jul 5;267(19):13383–13390. [PubMed] [Google Scholar]
  34. Lew J., Huang Q. Q., Qi Z., Winkfein R. J., Aebersold R., Hunt T., Wang J. H. A brain-specific activator of cyclin-dependent kinase 5. Nature. 1994 Sep 29;371(6496):423–426. doi: 10.1038/371423a0. [DOI] [PubMed] [Google Scholar]
  35. Lew J., Winkfein R. J., Paudel H. K., Wang J. H. Brain proline-directed protein kinase is a neurofilament kinase which displays high sequence homology to p34cdc2. J Biol Chem. 1992 Dec 25;267(36):25922–25926. [PubMed] [Google Scholar]
  36. Lichtenberg-Kraag B., Mandelkow E. M., Biernat J., Steiner B., Schröter C., Gustke N., Meyer H. E., Mandelkow E. Phosphorylation-dependent epitopes of neurofilament antibodies on tau protein and relationship with Alzheimer tau. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5384–5388. doi: 10.1073/pnas.89.12.5384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Love S., Saitoh T., Quijada S., Cole G. M., Terry R. D. Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol. 1988 Jul;47(4):393–405. doi: 10.1097/00005072-198807000-00001. [DOI] [PubMed] [Google Scholar]
  38. Lowe J., Blanchard A., Morrell K., Lennox G., Reynolds L., Billett M., Landon M., Mayer R. J. Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease. J Pathol. 1988 May;155(1):9–15. doi: 10.1002/path.1711550105. [DOI] [PubMed] [Google Scholar]
  39. Mandelkow E. M., Drewes G., Biernat J., Gustke N., Van Lint J., Vandenheede J. R., Mandelkow E. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 1992 Dec 21;314(3):315–321. doi: 10.1016/0014-5793(92)81496-9. [DOI] [PubMed] [Google Scholar]
  40. Manetto V., Perry G., Tabaton M., Mulvihill P., Fried V. A., Smith H. T., Gambetti P., Autilio-Gambetti L. Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative diseases. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4501–4505. doi: 10.1073/pnas.85.12.4501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Meyerson M., Enders G. H., Wu C. L., Su L. K., Gorka C., Nelson C., Harlow E., Tsai L. H. A family of human cdc2-related protein kinases. EMBO J. 1992 Aug;11(8):2909–2917. doi: 10.1002/j.1460-2075.1992.tb05360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Miller C. C., Brion J. P., Calvert R., Chin T. K., Eagles P. A., Downes M. J., Flament-Durand J., Haugh M., Kahn J., Probst A. Alzheimer's paired helical filaments share epitopes with neurofilament side arms. EMBO J. 1986 Feb;5(2):269–276. doi: 10.1002/j.1460-2075.1986.tb04209.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Nixon R. A., Sihag R. K. Neurofilament phosphorylation: a new look at regulation and function. Trends Neurosci. 1991 Nov;14(11):501–506. doi: 10.1016/0166-2236(91)90062-y. [DOI] [PubMed] [Google Scholar]
  44. Nukina N., Kosik K. S., Selkoe D. J. Recognition of Alzheimer paired helical filaments by monoclonal neurofilament antibodies is due to crossreaction with tau protein. Proc Natl Acad Sci U S A. 1987 May;84(10):3415–3419. doi: 10.1073/pnas.84.10.3415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Pappolla M. A. Lewy bodies of Parkinson's disease. Immune electron microscopic demonstration of neurofilament antigens in constituent filaments. Arch Pathol Lab Med. 1986 Dec;110(12):1160–1163. [PubMed] [Google Scholar]
  46. Paudel H. K., Lew J., Ali Z., Wang J. H. Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments. J Biol Chem. 1993 Nov 5;268(31):23512–23518. [PubMed] [Google Scholar]
  47. Perry R. H., Irving D., Blessed G., Fairbairn A., Perry E. K. Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci. 1990 Feb;95(2):119–139. doi: 10.1016/0022-510x(90)90236-g. [DOI] [PubMed] [Google Scholar]
  48. Pollanen M. S., Bergeron C., Weyer L. Characterization of a shared epitope in cortical Lewy body fibrils and Alzheimer paired helical filaments. Acta Neuropathol. 1994;88(1):1–6. doi: 10.1007/BF00294352. [DOI] [PubMed] [Google Scholar]
  49. Pollanen M. S., Dickson D. W., Bergeron C. Pathology and biology of the Lewy body. J Neuropathol Exp Neurol. 1993 May;52(3):183–191. doi: 10.1097/00005072-199305000-00001. [DOI] [PubMed] [Google Scholar]
  50. Schmidt M. L., Murray J., Lee V. M., Hill W. D., Wertkin A., Trojanowski J. Q. Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol. 1991 Jul;139(1):53–65. [PMC free article] [PubMed] [Google Scholar]
  51. Trojanowski J. Q., Schmidt M. L., Shin R. W., Bramblett G. T., Rao D., Lee V. M. Altered tau and neurofilament proteins in neuro-degenerative diseases: diagnostic implications for Alzheimer's disease and Lewy body dementias. Brain Pathol. 1993 Jan;3(1):45–54. doi: 10.1111/j.1750-3639.1993.tb00725.x. [DOI] [PubMed] [Google Scholar]
  52. Tsai L. H., Delalle I., Caviness V. S., Jr, Chae T., Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature. 1994 Sep 29;371(6496):419–423. doi: 10.1038/371419a0. [DOI] [PubMed] [Google Scholar]
  53. Tsai L. H., Takahashi T., Caviness V. S., Jr, Harlow E. Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development. 1993 Dec;119(4):1029–1040. doi: 10.1242/dev.119.4.1029. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES