Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathology
Abstract
Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.
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A reduced plaque burden has been shown to be accompanied by a reduced glial activation.
“a reduced plaque burden has been shown to be accompanied by a reduced glial activation [6], [60].”
From Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease (2014) · cites this paper as [6]
A reduced plaque load has been positively correlated with better performances in behavioral tests.
“A reduced plaque load has been positively correlated with better performances in behavioral tests [6], [57].”
From Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease (2014) · cites this paper as [6]
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · see citing works
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210 · see citing works
Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & Ihara, Y. (1994) · Neuron · doi:10.1016/0896-6273(94)90458-8 · Cited by 1,774 · see citing works
Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H., & Younkin, S. G. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00372.2001 · Cited by 1,053 · see citing works
Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
Jacobsen, J. S., Wu, C.-C., Redwine, J. M., Comery, T. A., Arias, R., Bowlby, M., Martone, R., Morrison, J. H., Pangalos, M. N., Reinhart, P. H., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600948103 · Cited by 701 · see citing works
Saido, T. C., Iwatsubo, T., Mann, D. M. A., Shimada, H., Ihara, Y., & Kawashima, S. (1995) · Neuron · doi:10.1016/0896-6273(95)90301-1 · Cited by 587 · see citing works
Näslund, J., Schierhorn, A., Hellman, U., Lannfelt, L., Roses, A. D., Tjernberg, L. O., Silberring, J., Gandy, S. E., Winblad, B., & Greengard, P. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.18.8378 · Cited by 468 · see citing works
Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in down Syndrome
Iwatsubo, T., Mann, D. M. A., Odaka, A., Suzuki, N., & Ihara, Y. (1995) · Annals of Neurology · doi:10.1002/ana.410370305 · Cited by 380 · see citing works
Amino-terminal Deletions Enhance Aggregation of β-Amyloid Peptides in Vitro
Pike, C. J., Overman, M. J., & Cotman, C. W. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.41.23895 · Cited by 302 · see citing works
Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain
Saido, T. C., Yamao-Harigaya, W., Iwatsubo, T., & Kawashima, S. (1996) · Neuroscience Letters · doi:10.1016/0304-3940(96)12970-0 · Cited by 270 · see citing works
Hutter‐Paier, B., Huttunen, H. J., Puglielli, L., Eckman, C. B., Kim, D. Y., Hofmeister, A., Moir, R. D., Domnitz, S. B., Frosch, M. P., Windisch, M., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.043 · Cited by 268 · see citing works
Self-citationOn the Seeding and Oligomerization of pGlu-Amyloid Peptides (<i>in vitro</i>)
Schilling, S., Lauber, T., Schaupp, M., Manhart, S., Scheel, E., Böhm, G., & Demuth, H.-U. (2006) · Biochemistry · doi:10.1021/bi0612667 · Cited by 254 · see citing works
Self-citationRockenstein, E. M., Mallory, M. E., Mante, M., Sisk, A., & Masliaha, E. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.1247 · Cited by 224 · see citing works
Hashimoto, T., Wakabayashi, T., Watanabe, A., Kowa, H., Hosoda, R., Nakamura, A., Kanazawa, I., Arai, T., Takio, K., Mann, D. M. A., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/21.7.1524 · Cited by 223 · see citing works
Comery, T. A., Martone, R. L., Aschmies, S., Atchison, K. P., Diamantidis, G., Gong, X., Zhou, H., Kreft, A. F., Pangalos, M. N., Sonnenberg‐Reines, J., et al. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2693-05.2005 · Cited by 214 · see citing works
Russo, C., Violani, E., Salis, S., Venezia, V., Dolcini, V., Damonte, G., Benatti, U., D’Arrigo, C., Patrone, E., Carlo, P., et al. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01107.x · Cited by 201 · see citing works
β-Amyloid Is Different in Normal Aging and in Alzheimer Disease
Piccini, A., Russo, C., Gliozzi, A., Relini, A., Vitali, A., Borghi, R., Giliberto, L., Armirotti, A., D’Arrigo, C., Bachi, A., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501694200 · Cited by 193 · see citing works
Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions
Schilling, S., Hoffmann, T., Manhart, S., Hoffmann, M., & Demuth, H. (2004) · FEBS Letters · doi:10.1016/s0014-5793(04)00300-x · Cited by 172 · see citing works
Self-citationPresenilin-1 mutations in Alzheimer's disease
Russo, C., Schettini, G., Saido, T. C., Hulette, C. M., Lippa, C. F., Lannfelt, L., Ghetti, B. F., Gambetti, P., Tabaton, M., & Teller, J. K. (2000) · Nature · doi:10.1038/35014735 · Cited by 156 · see citing works
Amino-Terminally Truncated Aβ Peptide Species Are the Main Component of Cotton Wool Plaques
Miravalle, L., Calero, M., Takao, M., Roher, A. E., Ghetti, B. F., & Vidal, R. (2005) · Biochemistry · doi:10.1021/bi0508237 · Cited by 140 · see citing works
Alzheimer’s Disease as Proteolytic Disorders: Anabolism and Catabolism of β-Amyloid
Saido, T. C. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(98)00033-5 · Cited by 140 · see citing works
The amyloid cascade hypothesis
Korczyn, A. D. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2007.11.008 · Cited by 136 · see citing works
Synthesis and Structure-Activity Relationships
勁一郎, 西., & Sasaki, M. (1998) · Journal of Pesticide Science · doi:10.1584/jpestics.23.429 · Cited by 108 · see citing works
Primary structure and functional expression of a glutaminyl cyclase.
Pohl, T., Zimmer, M., Mugele, K., & Spiess, J. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.22.10059 · Cited by 102 · see citing works
Buchholz, M., Heiser, U. F., Schilling, S., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050756e · Cited by 99 · see citing works
Self-citationLiu, K., Solano, I., Mann, D. M. A., Lemere, C. A., Mercken, M. H., Trojanowski, J. Q., & Lee, V. M. ‐. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0077-5 · Cited by 94 · see citing works
Inhibition of glutaminyl cyclase alters pyroglutamate formation in mammalian cells
Cynis, H., Schilling, S., Bodnár, M., Hoffmann, T., Heiser, U. F., Saido, T. C., & Demuth, H. (2006) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2006.08.003 · Cited by 85 · see citing works
Self-citationVanderstichele, H., Meyer, G. D., Andreasen, N., Kostanjevečki, V., Wallin, A., Olsson, A., Blennow, K., & Vanmechelen, E. (2005) · Clinical Chemistry · doi:10.1373/clinchem.2005.051201 · Cited by 80 · see citing works
Yu, L., Vizel, A., Huff, M. B., et al. (2006) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2006.05.008 · Cited by 77 · see citing works
Schilling, S., Appl, T., Hoffmann, T., Cynis, H., Schulz, K., Jagla, W., Friedrich, D., Wermann, M., Buchholz, M., Heiser, U. F., et al. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05471.x · Cited by 76 · see citing works
Self-citationRusso, C., Salis, S., Dolcini, V., Venezia, V., Song, X., Teller, J. K., & Schettini, G. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0357 · Cited by 75 · see citing works
Tomidokoro, Y., Lashley, T., Rostagno, A., Neubert, T. A., Bojsen-Møller, M., Braendgaard, H., Plant, G., Holton, J., Frangione, B., Révész, T., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504038200 · Cited by 68 · see citing works
Evidence for tissue‐specific forms of glutaminyl cyclase
Sykes, P. A., Watson, S. J., Temple, J. S., et al. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00872-8 · Cited by 53 · see citing works
Reimers, S., Hartlage‐Rübsamen, M., Brückner, G., & Roßner, S. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05514.x · Cited by 38 · see citing works
Generation of amyloid β peptide with pyroglutamate at position 3 in primary cortical neurons
Shirotani, K., Tsubuki, S., Lee, H.-J., Maruyama, K., & Saido, T. C. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00351-8 · Cited by 28 · see citing works
Chromosome 13 dementia syndromes as models of neurodegeneration
Ghiso, J. A., Révész, T., Holton, J. L., Rostagno, A. A., Lashley, T., Houlden, H., Gibb, G., Anderton, B. H., Bek, T., Bojsen‐Møller, M., et al. (2001) · Amyloid · doi:10.3109/13506120108993826 · Cited by 26 · see citing works
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Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers‐Nolten, I., Van Der Werf, K., Subramaniam, V., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.211 · Cited by 532 · see citing works
A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice
DeMattos, R. B., Lu, J., Tang, Y., Racke, M. M., DeLong, C. A., Tzaferis, J. A., Hole, J. T., Forster, B. M., McDonnell, P. C., Liu, F., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.10.029 · Cited by 442 · see citing works
Santos-Martins, D., Forli, S., Ramos, M. J., & Olson, A. J. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500209e · Cited by 318 · see citing works
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Schlenzig, D., Manhart, S., Cinar, Y., Kleinschmidt, M., Hause, G., Willbold, D., Funke, S. A., Schilling, S., & Demuth, H.-U. (2009) · Biochemistry · doi:10.1021/bi900818a · Cited by 228 · see citing works
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Ichikawa, S., Flaxman, H. A., Xu, W., Vallavoju, N., Lloyd, H. C., Wang, B., Shen, D., Pratt, M. R., & Woo, C. M. (2022) · Nature · doi:10.1038/s41586-022-05333-5 · Cited by 195 · see citing works
Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H.-U., & Bayer, T. A. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0557-5 · Cited by 174 · see citing works
Self-citationChami, L., & Checler, F. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-52 · Cited by 168 · see citing works
Morawski, M., Brückner, G., Jäger, C., Seeger, G., Matthews, R. T., & Arendt, T. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2011.00557.x · Cited by 157 · see citing works
Rajasekhar, K., & Govindaraju, T. (2018) · RSC Advances · doi:10.1039/c8ra03620a · Cited by 150 · see citing works
Bhattacharya, S., Haertel, C., Maelicke, A., & Montag, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089454 · Cited by 142 · see citing works
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Wirths, O., Bethge, T., Marcello, A., Harmeier, A., Jawhar, S., Lucassen, P. J., Multhaup, G., Brody, D. L., Esparza, T., Ingelsson, M., et al. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-009-0314-x · Cited by 106 · see citing works
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Wirths, O., Erck, C., Martens, H., Harmeier, A., Geumann, C., Jawhar, S., Kumar, S., Multhaup, G., Walter, J., Ingelsson, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178707 · Cited by 103 · see citing works
Alexandru, A., Jagla, W., Graubner, S., Becker, A., Bäuscher, C., Kohlmann, S., Sedlmeier, R., Raber, K. A., Cynis, H., Rönicke, R., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.1794-11.2011 · Cited by 102 · see citing works
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Self-citation
- Authors
- Schilling, S., Zeitschel, U., Hoffmann, T., Heiser, U., Francke, M., Kehlen, A., Holzer, M., Hutter-Paier, B., Prokesch, M., Windisch, M., Jagla, W., Schlenzig, D., Lindner, C., Rudolph, T., Reuter, G., Cynis, H., Montag, D., Demuth, H.-U., & Rossner, S.
- Affiliations
- Probiodrug (Germany) (DE)
- Leipzig University (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Leibniz Institute for Neurobiology (DE)
- Corresponding author
- Demuth, Hans-Ulrich
- ORCID
- Venue
- Nature Medicine
- Published
- 2008-09-28
- Volume
- 14
- Issue
- 10
- Pages
- 1106-1111
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1990632702
- Cited by
- 357
- References
- 37
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 15 · 2023: 13 · 2022: 15 · 2021: 25 · 2020: 15 · 2019: 15 · 2018: 23 · 2017: 16 · 2016: 20 · 2015: 23 · 2014: 32 · 2013: 27 · 2012: 26
- FWCI
- 15.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- glutaminyl cyclase, pyroglutamate amyloid-beta, Alzheimer's disease, enzyme inhibition, amyloid-beta aggregation, amyloid plaques, transgenic mouse model, Drosophila model, learning and memory, gliosis, familial Danish dementia, amyloidosis, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Humans, Memory, Mice, Transgenic, Pyrrolidonecarboxylic Acid, Amyloid beta-Peptides, Aminoacyltransferases, Mice
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