Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. (original) (raw)
Proc Natl Acad Sci U S A. 1996 Oct 1; 93(20): 11213–11218.
Cambridge Brain Bank Laboratory, University Department of Psychiatry, United Kingdom.
Abstract
In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases. We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases. We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain. Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have Ki values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain. Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.
Full text
Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
Images in this article
Click on the image to see a larger version.
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, 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. [PMC free article] [PubMed] [Google Scholar]
- Harrington CR, Mukaetova-Ladinska EB, Hills R, Edwards PC, Montejo de Garcini E, Novak M, Wischik CM. 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. [PMC free article] [PubMed] [Google Scholar]
- Mukaetova-Ladinska EB, Harrington CR, Roth M, Wischik CM. Biochemical and anatomical redistribution of tau protein in Alzheimer's disease. Am J Pathol. 1993 Aug;143(2):565–578. [PMC free article] [PubMed] [Google Scholar]
- Lai RY, Gertz HN, Wischik DJ, Xuereb JH, Mukaetova-Ladinska EB, Harrington CR, Edwards PC, Mena R, Paykel ES, Brayne C, et al. Examination of phosphorylated tau protein as a PHF-precursor at early stage Alzheimer's disease. Neurobiol Aging. 1995 May-Jun;16(3):433–445. [PubMed] [Google Scholar]
- Bondareff W, Wischik CM, Novak M, Amos WB, 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]
- Kosik KS, Orecchio LD, Binder L, Trojanowski JQ, Lee VM, Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron. 1988 Nov;1(9):817–825. [PubMed] [Google Scholar]
- Mena R, Edwards PC, Harrington CR, Mukaetova-Ladinska EB, Wischik CM. Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer's disease. Acta Neuropathol. 1996;91(6):633–641. [PubMed] [Google Scholar]
- Mena R, Wischik CM, Novak M, Milstein C, Cuello AC. A progressive deposition of paired helical filaments (PHF) in the brain characterizes the evolution of dementia in Alzheimer's disease. An immunocytochemical study with a monoclonal antibody against the PHF core. J Neuropathol Exp Neurol. 1991 Jul;50(4):474–490. [PubMed] [Google Scholar]
- Bondareff W, Mountjoy CQ, Wischik CM, Hauser DL, LaBree LD, Roth M. Evidence of subtypes of Alzheimer's disease and implications for etiology. Arch Gen Psychiatry. 1993 May;50(5):350–356. [PubMed] [Google Scholar]
- McKee AC, Kowall NW, Kosik KS. Microtubular reorganization and dendritic growth response in Alzheimer's disease. Ann Neurol. 1989 Nov;26(5):652–659. [PubMed] [Google Scholar]
- Wilcock GK, Esiri MM, Bowen DM, Smith CC. Alzheimer's disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci. 1982 Dec;57(2-3):407–417. [PubMed] [Google Scholar]
- Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology. 1992 Sep;42(9):1681–1688. [PubMed] [Google Scholar]
- Montejo de Garcini E, Serrano L, Avila J. Self assembly of microtubule associated protein tau into filaments resembling those found in Alzheimer disease. Biochem Biophys Res Commun. 1986 Dec 15;141(2):790–796. [PubMed] [Google Scholar]
- Wille H, Drewes G, Biernat J, Mandelkow EM, Mandelkow E. Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J Cell Biol. 1992 Aug;118(3):573–584. [PMC free article] [PubMed] [Google Scholar]
- Crowther RA, Olesen OF, Jakes R, Goedert M. The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer's disease. FEBS Lett. 1992 Sep 7;309(2):199–202. [PubMed] [Google Scholar]
- Ruben GC, Iqbal K, Grundke-Iqbal I, Johnson JE., Jr The organization of the microtubule associated protein tau in Alzheimer paired helical filaments. Brain Res. 1993 Jan 29;602(1):1–13. [PubMed] [Google Scholar]
- Troncoso JC, Costello A, Watson AL, Jr, Johnson GV. In vitro polymerization of oxidized tau into filaments. Brain Res. 1993 Jun 11;613(2):313–316. [PubMed] [Google Scholar]
- García de Ancos J, Correas I, Avila J. Differences in microtubule binding and self-association abilities of bovine brain tau isoforms. J Biol Chem. 1993 Apr 15;268(11):7976–7982. [PubMed] [Google Scholar]
- Crowther RA, Olesen OF, Smith MJ, Jakes R, Goedert M. Assembly of Alzheimer-like filaments from full-length tau protein. FEBS Lett. 1994 Jan 10;337(2):135–138. [PubMed] [Google Scholar]
- Jakes R, Novak M, Davison M, Wischik CM. Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer's disease. EMBO J. 1991 Oct;10(10):2725–2729. [PMC free article] [PubMed] [Google Scholar]
- Novak M, Kabat J, Wischik CM. Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J. 1993 Jan;12(1):365–370. [PMC free article] [PubMed] [Google Scholar]
- Ksiezak-Reding H, Yen SH. Structural stability of paired helical filaments requires microtubule-binding domains of tau: a model for self-association. Neuron. 1991 May;6(5):717–728. [PubMed] [Google Scholar]
- Schweers O, Mandelkow EM, Biernat J, Mandelkow E. Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8463–8467. [PMC free article] [PubMed] [Google Scholar]
- Wilson DM, Binder LI. Polymerization of microtubule-associated protein tau under near-physiological conditions. J Biol Chem. 1995 Oct 13;270(41):24306–24314. [PubMed] [Google Scholar]
- Wischik CM, Crowther RA, Stewart M, Roth M. Subunit structure of paired helical filaments in Alzheimer's disease. J Cell Biol. 1985 Jun;100(6):1905–1912. [PMC free article] [PubMed] [Google Scholar]
- Crowther RA, Wischik CM. Image reconstruction of the Alzheimer paired helical filament. EMBO J. 1985 Dec 30;4(13B):3661–3665. [PMC free article] [PubMed] [Google Scholar]
- Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA. 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. [PMC free article] [PubMed] [Google Scholar]
- Novak M, Jakes R, Edwards PC, Milstein C, Wischik CM. 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. [PMC free article] [PubMed] [Google Scholar]
- Caputo CB, Wischik C, Novak M, Scott CW, Brunner WF, De Garcini EM, Lo MM, Norris TE, Salama AI. Immunological characterization of the region of tau protein that is bound to Alzheimer paired helical filaments. Neurobiol Aging. 1992 Mar-Apr;13(2):267–274. [PubMed] [Google Scholar]
- Goedert M, Wischik CM, Crowther RA, Walker JE, 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. [PMC free article] [PubMed] [Google Scholar]
- Harrington CR, Wischik CM, McArthur FK, Taylor GA, Edwardson JA, Candy JM. Alzheimer's-disease-like changes in tau protein processing: association with aluminium accumulation in brains of renal dialysis patients. Lancet. 1994 Apr 23;343(8904):993–997. [PubMed] [Google Scholar]
- Harrington CR, Louwagie J, Rossau R, Vanmechelen E, Perry RH, Perry EK, Xuereb JH, Roth M, Wischik CM. Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease. Am J Pathol. 1994 Dec;145(6):1472–1484. [PMC free article] [PubMed] [Google Scholar]
- Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. 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. [PubMed] [Google Scholar]
- Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron. 1993 Jul;11(1):153–163. [PubMed] [Google Scholar]
- Harrington CR. Lowry protein assay containing sodium dodecyl sulfate in microtiter plates for protein determinations on fractions from brain tissue. Anal Biochem. 1990 May 1;186(2):285–287. [PubMed] [Google Scholar]
- Harrington CR, Edwards PC, Wischik CM. Competitive ELISA for the measurement of tau protein in Alzheimer's disease. J Immunol Methods. 1990 Dec 5;134(2):261–271. [PubMed] [Google Scholar]
- Trojanowski JQ, Lee VM. Phosphorylation of paired helical filament tau in Alzheimer's disease neurofibrillary lesions: focusing on phosphatases. FASEB J. 1995 Dec;9(15):1570–1576. [PubMed] [Google Scholar]
- DiSanto AR, Wagner JG. Pharmacokinetics of highly ionized drugs. II. Methylene blue--absorption, metabolism, and excretion in man and dog after oral administration. J Pharm Sci. 1972 Jul;61(7):1086–1090. [PubMed] [Google Scholar]
- Naylor GJ, Martin B, Hopwood SE, Watson Y. A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry. 1986 Aug;21(10):915–920. [PubMed] [Google Scholar]
- Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754–760. [PubMed] [Google Scholar]
- Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973–977. [PubMed] [Google Scholar]
- Jobst KA, Smith AD, Szatmari M, Esiri MM, Jaskowski A, Hindley N, McDonald B, Molyneux AJ. Rapidly progressing atrophy of medial temporal lobe in Alzheimer's disease. Lancet. 1994 Apr 2;343(8901):829–830. [PubMed] [Google Scholar]
- Müller T. Light-microscopic demonstration of methylene blue accumulation sites in mouse brain after supravital staining. Acta Anat (Basel) 1992;144(1):39–44. [PubMed] [Google Scholar]
Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences