Abstract
Antibodies directed against three regions of tau have been used in a histologic study of granulovacuolar degeneration (GVD) in Alzheimer's disease (AD). Granulovascular degeneration complexes, consisting of a dense granule in a less-dense vacuole, were found in hippocampal pyramidal neurons in all patients studied. Anti-tau antibodies directed against the N-and C-termini, and the repeat region of tau, were found to immunolabel the granule of the GVD complex. Intracellular neurofibrillary tangles also were labeled by these antibodies. In particular, MAb6.423, which recognizes tau protein sequestered in paired helical filaments (PHF) in AD, but not the normal tau proteins so far described in human brain, labeled GVD granules. Contrarily, a generic tau marker (MAb7.51), which immunolabels all known isoforms of isolated and expressed tau protein, including PHF-tau, did not label the GVD granule. These findings demonstrate that the entire tau molecule is sequestered within the GVD granule, and that the tau protein found in GVD complexes is antigenically related to that found in PHFs. There is, however, a difference in the way in which the repeat region of tau is incorporated into the two structures, making the MAb7.51 epitope unavailable in the GVD complex. These findings suggest that the formation of GVD complexes in hippocampal pyramidal neurons vulnerable to neurofibrillary degeneration may represent an alternative pathway for dealing with an aberrant molecular complex, which contributes to the formation of GVD granules and neurofibrillary tangles in AD.
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Selected References
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- Ball M. J., Lo P. Granulovacuolar degeneration in the ageing brain and in dementia. J Neuropathol Exp Neurol. 1977 May;36(3):474–487. doi: 10.1097/00005072-197705000-00006. [DOI] [PubMed] [Google Scholar]
- Ball M. J. Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol. 1977 Feb 28;37(2):111–118. doi: 10.1007/BF00692056. [DOI] [PubMed] [Google Scholar]
- Ball M. J., Nuttall K. Topography of neurofibrillary tangles and granulovacuoles in hippocampi of patients with Down's syndrome: quantitative comparison with normal ageing and Alzheimer's disease. Neuropathol Appl Neurobiol. 1981 Jan-Feb;7(1):13–20. doi: 10.1111/j.1365-2990.1981.tb00228.x. [DOI] [PubMed] [Google Scholar]
- Bondareff W., Wischik C. M., Novak M., Amos W. B., Klug A., Roth M. Molecular analysis of neurofibrillary degeneration in Alzheimer's disease. An immunohistochemical study. Am J Pathol. 1990 Sep;137(3):711–723. [PMC free article] [PubMed] [Google Scholar]
- Cole G. M., Timiras P. S. Ubiquitin-protein conjugates in Alzheimer's lesions. Neurosci Lett. 1987 Aug 18;79(1-2):207–212. doi: 10.1016/0304-3940(87)90698-7. [DOI] [PubMed] [Google Scholar]
- Delacourte A., Defossez A. Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J Neurol Sci. 1986 Dec;76(2-3):173–186. doi: 10.1016/0022-510x(86)90167-x. [DOI] [PubMed] [Google Scholar]
- Dickson D. W., Ksiezak-Reding H., Davies P., Yen S. H. A monoclonal antibody that recognizes a phosphorylated epitope in Alzheimer neurofibrillary tangles, neurofilaments and tau proteins immunostains granulovacuolar degeneration. Acta Neuropathol. 1987;73(3):254–258. doi: 10.1007/BF00686619. [DOI] [PubMed] [Google Scholar]
- Galloway P. G., Mulvihill P., Siedlak S., Mijares M., Kawai M., Padget H., Kim R., Perry G. Immunochemical demonstration of tropomyosin in the neurofibrillary pathology of Alzheimer's disease. Am J Pathol. 1990 Aug;137(2):291–300. [PMC free article] [PubMed] [Google Scholar]
- Gambetti P., Shecket G., Ghetti B., Hirano A., Dahl D. Neurofibrillary changes in human brain. An immunocytochemical study with a neurofilament antiserum. J Neuropathol Exp Neurol. 1983 Jan;42(1):69–79. doi: 10.1097/00005072-198301000-00006. [DOI] [PubMed] [Google Scholar]
- Goedert M., Spillantini M. G., Jakes R., Rutherford D., Crowther R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989 Oct;3(4):519–526. doi: 10.1016/0896-6273(89)90210-9. [DOI] [PubMed] [Google Scholar]
- Goedert M., Spillantini M. G., Potier M. C., Ulrich J., Crowther R. A. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 1989 Feb;8(2):393–399. doi: 10.1002/j.1460-2075.1989.tb03390.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goedert M., Wischik C. M., Crowther R. A., Walker J. E., Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988 Jun;85(11):4051–4055. doi: 10.1073/pnas.85.11.4051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., Binder L. I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HIRANO A., MALAMUD N., KURLAND L. T. Parkinsonism-dementia complex, an endemic disease on the island of Guam. II. Pathological features. Brain. 1961 Dec;84:662–679. doi: 10.1093/brain/84.4.662. [DOI] [PubMed] [Google Scholar]
- Harrington C. R., Mukaetova-Ladinska E. B., Hills R., Edwards P. C., Montejo de Garcini E., Novak M., Wischik C. M. Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5842–5846. doi: 10.1073/pnas.88.13.5842. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirano A., Dembitzer H. M., Kurland L. T., Zimmerman H. M. The fine structure of some intraganglionic alterations. Neurofibrillary tangles, granulovacuolar bodies and "rod-like" structures as seen in Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. J Neuropathol Exp Neurol. 1968 Apr;27(2):167–182. [PubMed] [Google Scholar]
- Hirano A., Tuazon R., Zimmerman H. M. Neurofibrillary changes, granulovacuolar bodies and argentophilic globules observed in tuberous sclerosis. Acta Neuropathol. 1968 Sep 25;11(3):257–261. doi: 10.1007/BF00692311. [DOI] [PubMed] [Google Scholar]
- Joachim C. L., Morris J. H., Selkoe D. J., Kosik K. S. Tau epitopes are incorporated into a range of lesions in Alzheimer's disease. J Neuropathol Exp Neurol. 1987 Nov;46(6):611–622. doi: 10.1097/00005072-198711000-00001. [DOI] [PubMed] [Google Scholar]
- Kahn J., Anderton B. H., Probst A., Ulrich J., Esiri M. M. Immunohistological study of granulovacuolar degeneration using monoclonal antibodies to neurofilaments. J Neurol Neurosurg Psychiatry. 1985 Sep;48(9):924–926. doi: 10.1136/jnnp.48.9.924. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kosik K. S., Duffy L. K., Dowling M. M., Abraham C., McCluskey A., Selkoe D. J. Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7941–7945. doi: 10.1073/pnas.81.24.7941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kosik K. S., Joachim C. L., Selkoe D. J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044–4048. doi: 10.1073/pnas.83.11.4044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kosik K. S., Orecchio L. D., Binder L., Trojanowski J. Q., Lee V. M., Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron. 1988 Nov;1(9):817–825. doi: 10.1016/0896-6273(88)90129-8. [DOI] [PubMed] [Google Scholar]
- Ksiezak-Reding H., Yen S. H. Two monoclonal antibodies recognize Alzheimer's neurofibrillary tangles, neurofilament, and microtubule-associated proteins. J Neurochem. 1987 Feb;48(2):455–462. doi: 10.1111/j.1471-4159.1987.tb04114.x. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Mori H., Kondo J., Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science. 1987 Mar 27;235(4796):1641–1644. doi: 10.1126/science.3029875. [DOI] [PubMed] [Google Scholar]
- Mulvihill P., Perry G. Immunoaffinity demonstration that paired helical filaments of Alzheimer disease share epitopes with neurofilaments, MAP2 and tau. Brain Res. 1989 Apr 10;484(1-2):150–156. doi: 10.1016/0006-8993(89)90357-0. [DOI] [PubMed] [Google Scholar]
- Novak M., Jakes R., Edwards P. C., Milstein C., Wischik C. M. Difference between the tau protein of Alzheimer paired helical filament core and normal tau revealed by epitope analysis of monoclonal antibodies 423 and 7.51. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5837–5841. doi: 10.1073/pnas.88.13.5837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Novak M., Wischik C. M., Edwards P., Pannell R., Milstein C. Characterisation of the first monoclonal antibody against the pronase resistant core of the Alzheimer PHF. Prog Clin Biol Res. 1989;317:755–761. [PubMed] [Google Scholar]
- Nukina N., Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem. 1986 May;99(5):1541–1544. doi: 10.1093/oxfordjournals.jbchem.a135625. [DOI] [PubMed] [Google Scholar]
- Perry G., Friedman R., Shaw G., Chau V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A. 1987 May;84(9):3033–3036. doi: 10.1073/pnas.84.9.3033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Perry G., Mulvihill P., Fried V. A., Smith H. T., Grundke-Iqbal I., Iqbal K. Immunochemical properties of ubiquitin conjugates in the paired helical filaments of Alzheimer disease. J Neurochem. 1989 May;52(5):1523–1528. doi: 10.1111/j.1471-4159.1989.tb09203.x. [DOI] [PubMed] [Google Scholar]
- Perry G., Rizzuto N., Autilio-Gambetti L., Gambetti P. Paired helical filaments from Alzheimer disease patients contain cytoskeletal components. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3916–3920. doi: 10.1073/pnas.82.11.3916. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Price D. L., Altschuler R. J., Struble R. G., Casanova M. F., Cork L. C., Murphy D. B. Sequestration of tubulin in neurons in Alzheimer's disease. Brain Res. 1986 Oct 22;385(2):305–310. doi: 10.1016/0006-8993(86)91077-2. [DOI] [PubMed] [Google Scholar]
- STEELE J. C., RICHARDSON J. C., OLSZEWSKI J. PROGRESSIVE SUPRANUCLEAR PALSY. A HETEROGENEOUS DEGENERATION INVOLVING THE BRAIN STEM, BASAL GANGLIA AND CEREBELLUM WITH VERTICAL GAZE AND PSEUDOBULBAR PALSY, NUCHAL DYSTONIA AND DEMENTIA. Arch Neurol. 1964 Apr;10:333–359. doi: 10.1001/archneur.1964.00460160003001. [DOI] [PubMed] [Google Scholar]
- Shaw G., Chau V. Ubiquitin and microtubule-associated protein tau immunoreactivity each define distinct structures with differing distributions and solubility properties in Alzheimer brain. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2854–2858. doi: 10.1073/pnas.85.8.2854. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tomlinson B. E., Kitchener D. Granulovacuolar degeneration of hippocampal pyramidal cells. J Pathol. 1972 Mar;106(3):165–185. doi: 10.1002/path.1711060305. [DOI] [PubMed] [Google Scholar]
- Wang G. P., Grundke-Iqbal I., Kascsak R. J., Iqbal K., Wisniewski H. M. Alzheimer neurofibrillary tangles: monoclonal antibodies to inherent antigen(s). Acta Neuropathol. 1984;62(4):268–275. doi: 10.1007/BF00687608. [DOI] [PubMed] [Google Scholar]
- Wischik C. M. Cell biology of the Alzheimer tangle. Curr Opin Cell Biol. 1989 Feb;1(1):115–122. doi: 10.1016/s0955-0674(89)80047-x. [DOI] [PubMed] [Google Scholar]
- Wischik C. M., Crowther R. A., Stewart M., Roth M. Subunit structure of paired helical filaments in Alzheimer's disease. J Cell Biol. 1985 Jun;100(6):1905–1912. doi: 10.1083/jcb.100.6.1905. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wischik C. M., Novak M., Edwards P. C., Klug A., Tichelaar W., Crowther R. A. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4884–4888. doi: 10.1073/pnas.85.13.4884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wischik C. M., Novak M., Thøgersen H. C., Edwards P. C., Runswick M. J., Jakes R., Walker J. E., Milstein C., Roth M., Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4506–4510. doi: 10.1073/pnas.85.12.4506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolozin B. L., Pruchnicki A., Dickson D. W., Davies P. A neuronal antigen in the brains of Alzheimer patients. Science. 1986 May 2;232(4750):648–650. doi: 10.1126/science.3083509. [DOI] [PubMed] [Google Scholar]
- Wood J. G., Mirra S. S., Pollock N. J., Binder L. I. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau) Proc Natl Acad Sci U S A. 1986 Jun;83(11):4040–4043. doi: 10.1073/pnas.83.11.4040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yen S. H., Gaskin F., Fu S. M. Neurofibrillary tangles in senile dementia of the Alzheimer type share an antigenic determinant with intermediate filaments of the vimentin class. Am J Pathol. 1983 Dec;113(3):373–381. [PMC free article] [PubMed] [Google Scholar]