Abstract
Corticobasal degeneration (CBD) is a rare, progressive neurological disorder characterized by widespread neuronal and glial accumulation of abnormal tau protein. Using immunohistochemistry we analyzed tau epitope expression and phosphorylation state in CBD and compared them to cytoskeletal changes in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Epitopes spanning the entire length of the tau protein were present in CBD inclusions. An antibody against the alternatively spliced exon 3 did not recognize cytoskeletal lesions in CBD, but did in AD and PSP. Tau epitopes from each region of the molecule were present in cytoskeletal inclusions in CBD, including gray matter astrocytic plaques, gray and white matter threads, and oligodendroglial inclusions. As in AD, tau from CBD was highly phosphorylated. Antibodies that recognized phosphorylated tau epitopes reacted with material from CBD in a highly phosphatase-dependent manner. Again, all types of inclusions contained phosphorylated epitopes. We conclude that abnormal tau protein in CBD comprises the entire tau molecule and is highly phosphorylated, but is distinguished from AD and PSP by the paucity of epitopes contained in the alternatively spliced exon 3.
Similar content being viewed by others
References
Bancher C, Lassmann H, Budka H, Grundke-Iqbal I, Iqbak K, Wiche G, Seitelberger F, Wisniewski HM (1987) Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences. Acta Neuropathol (Berl) 74: 39–46
Biernat J, Mandelkow EM, Schroter C, Lichtenberg-Kragg B, Steiner B, Berling B, Meyer H, Mercken M, Vandermeeren A, Goedert M, Mandelkow E (1992) The switch of tau protein to an Alzhemier-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J 11: 1593–1597
Binder LI, Frankfurter A, Rebhun L (1985) The distribution of tau polypeptides in the mammalian central nervous system. J Cell Biol 101: 1371–1378
Cruz-Sanchez FF, Rossi ML, Cardozo A, Deacon P, Tolosa E (1992) Clinical and pathological study of two patients with progressive supranuclear palsy and Alzheimer's changes. Antigenic determinants that distinguish cortical and subcortical neurofibrillary tangles. Neurosci Lett 136: 43–46
Davies P, Ghanbari H, Issacs A, Dickson DW, Mattiace LA, Rosado M, Vincent IJ (1993) TG3: a better antibody than Alz-50 for the visualization of Alzheimer-type neuronal pathology (abstract). Soc Neurosci 1636
Dickson DW, Mattiace LA (1992) Immunocytochemical studies distinguish corticobasal degeneration from progressive supranuclear palsy (abstract). J Neuropathol Exp Neurol 51: 321
Dickson DW, Yen S-H, Horoupian DS (1986) Pick body-like inclusions in the dentate fascia of the hippocampus in Alzheimer's disease. Acta Neuropathol (Berl) 71: 38–45
Dickson DW, Ksiezak-Reding H, Liu WK, Davies P, Crowe A, Yen S-H (1992) Immunocytochemistry of neurofibrillary tangles with antibodies to subregions of tau protein: identification of hidden and cleaved tau epitopes and a new phosphorylation site. Acta Neuropathol 84: 596–605
Dickson DW, Liu W-K, Kress Y, Ku J, DeJesus O, Yen S-HC (1993) Phosphorylated tau immunoreactivity of granulovacuolar bodies (GVB) of Alzheimer's disease: localization of two amino-terminal tau epitopes in GVB. Acta Neuropathol 85: 463–470
Drubin DG, Kirschner MW (1986) Tau protein function in living cells. J Cell Biol 103: 2739–2746
Feany MB, Dickson DW (1995) Widespread cytoskeletal pathology characterize corticobasal degeneration. Am J Pathol 147 (in press)
Flament S, Delacourte A, Vernu M, Hauw J-J, Javoy-Agid F (1991) Abnormal tau proteins in progressive supranuclear palsy. Acta Neuropathol 81: 591–596
Gibb WRG, Luthert PJ, Marsden CD (1989) Corticobasal degeneration. Brain 112: 1171–1192
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3: 519–526
Goedert M, Spillantini MG, Cairns NY, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168
Greenberg SG, Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87: 5827–5831
Iwatsubo T, Hasegawa M, Ihara Y (1994) Neuronal and glial tau-positive inclusions in diverse neurologic disease share common phosphorylation characteristics. Acta Neuropathol 88: 129–136
Khachaturian ZS (1985) Diagnosis of Alzheimer's disease. Arch Neurol 42: 1097–1105
Kosik K, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (τ) is a major antigenic component of paired helical filaments in Alzheimer's disease. Proc Natl Acad Sci USA 83: 4044–4048
Kosik D, Orecchio KD, Binder LI, Trojanowski JQ, Lee VMY, Lee G (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1: 817–825
Ksiezak-Reding H, Morgan K, Mattiace LA, Davies P, Liu W-K, Yen S-H, Weidenheim K, Dickson DW (1994) Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration. Am J Pathol 145: 1–13
Lang AE, Riley DE, Bergeron C (1994) Cortico-basal ganglionic degeneration. In: Calne DB (ed) Neurodegenerative diseases. Saunders, Philadelphia, pp 877–894
Lerner A, Friedlan R, Riley D, Whitehouse P, Lanska D, Vick N, Cochran E, Tresser N, Cohen M, Gambetti P (1992) Dementia with pathological findings of cortical-basal degeneration (abstract). Ann Neurol 32: 271
Lippa CF, Smith TW, Fontneau N (1990) Corticonigral degeneration with neuronal achromasia. A clinicopathological study of two cases. J Neurol Sci 98: 301–310
Liu W-K, Ksiezak-Reding H, Yen S-H (1991) Abnormal tau proteins from Alzheimer's disease brains: purification and amino acid analysis. J Biol Chem 266: 21723–21727
Liu W-K, Dickson DW, Yen S-H (1993) Heterogeneity of tau protein in Alzheimer's disease. Am J Pathol 142: 387–394
Liu W-K, Dickson DW, Yen S-HC (1994) Amino acid residues 226–240 of τ, which encompass the first Lys-Ser-Pro site of τ, are partially phosphorylated in Alzheimer paired helical filament-τ. J Neurochem 62: 1055–1061
Matsuo ES, Shin R-W, Billingsley ML, Van de Voorde A, O'Connor M, Trojanowski JQ, Lee V M-Y (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau. Neuron 13: 989–1002
Mattiace LA, Wu E, Aronson M, Dickson DW (1991) A new neuritic plaque without amyloid in corticonigral degeneration with neuronal achromasia (abstract). J Neuropathol Exp Neurol 50:310
Mori H, Nishimura M, Namba Y, Oda M (1994) Corticobasal degeneration: a disease with widespread appearance of abnormal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy. Acta Neuropathol 88: 113–121
Paulus W, Selim M (1990) Corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles. Acta Neuropathol 81: 89–94
Probst A, Kangui D, Lautenschlager C, Ulrich J, Brion JP, Anderton BH (1988) Progressive supranuclear palsy: extensive neuropil threads in addition to neurofibrillary tangles. Acta Neuropathol 77: 61–68
Rebeiz JJ, Kolodny EH, Richardson EP (1967) Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 92: 23–26
Rebeiz JJ, Kolodny EH, Richardson EP (1968) Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18: 20–33
Roy S, Datta CK, Hirano A, Ghatak NR, Zimmerman HM (1974) Electron microscopic study of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome. Acta Neuropathol (Berl) 29: 175–179
Schmidt ML, Lee VM-Y, Hurtig H, Trojanowski JQ (1988) Properties of antigenic determinants that distinguish neurofibrillary tangles in progressive supranuclear palsy and Alzheimer's disease. Lab Invest 59: 460–466
Tellez-Nagel I, Wisiewski HM (1973) Ultrastructure of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome. Arch Neurol 29: 324–327
Wakabayashi K, Oyanagi K, Makifuchi T, Ikuta F, Honna A, Honna Y, Horikawa Y, Tokiguchi S (1994) Corticobasal degeneration: etiopathological significance of the cytoskeletal alterations. Acta Neuropathol 87: 545–553
Wolozin GL, Pruchnicki A, Dickson DW, Davies P (1986) A neuronal antigen in the brain of Alzheimer patients. Science 232: 648–650
Yen S-H, Crowe A, Dickson DW (1985) Monoclonal antibodies to Alzheimer neurofibrillary tangles. I. Identification of polypeptides. Am J Pathol 120: 282–291
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Feany, M.B., Ksiezak-Reding, H., Liu, W.K. et al. Epitope expression and hyperphosphorylation of tau protein in corticobasal degeneration: differentiation from progressive supranuclear palsy. Acta Neuropathol 90, 37–43 (1995). https://doi.org/10.1007/BF00294457
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00294457