Abstract
Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Aβ peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease1,2,3,4,5,6. 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 Aβ. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Aβ3(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 Aβx–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 Aβ3(pE)–42 acts as a seed for Aβ aggregation by self-aggregation and co-aggregation with Aβ1–40/42. Therefore, Aβ3(pE)–40/42 peptides seem to represent Aβ forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Aβ 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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Acknowledgements
We thank K. Sowa, R. Jendrek, K. Schulz, M. Bornack, E. Scheel and M. Buchholz for technical assistance. The authors would like to express their gratitude to K. Hsiao (University of Minnesota) for kindly providing Tg2576 mice and E. Masliah (University of California, San Diego) for providing the TASD-41 mice. Thanks are due to T.C. Saido (Riken Brain Science Institute) for the gift of the APP-NLE vector. S. Winter maintained and analyzed organotypic brain slice cultures from Tg2576 mice. We are also grateful to J. Heins for statistical analysis and to M.T. Stubbs, K. Glund and M. Hartlage-Rübsamen for helpful discussion. This work was supported by German Federal Department of Education, Science and Technology BMBF grant #3013185 to H.-U.D.
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T.H., S.S. and S.R. planned most of the experiments. S.S., H.C., T.H., A.K., D.S. and U.H. conducted most of the biochemical and cell biological investigations. S.S., A.K., W.J., M.F. and M.H. analyzed the human brain tissue. U.Z. and S.R. carried out the Tg2576 mouse experiments. M.P., B.H.-P. and M.W. performed the TASD-41 mouse experiments. D.M. conducted the behavioral analysis of Tg2576. C.L., T.R. and G.R. generated the transgenic Drosophila lines. S.R., S.S. and H.-U.D. designed the study and wrote the manuscript. H.-U.D. initiated the research and supervised the program.
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S.S., T.H., U.H., A.K., W.J., D.S., H.C. and H.-U.D. are employees of Probiodrug AG or Ingenium GmbH, a privately held biotechnology company in Germany. H.-U.D. holds shares in the united company. B.H.-P., M.P. and M.W. are employees of JSW-CRS Research, a privately owned contract research organization in Austria. M.W. holds stock in the company.
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Schilling, S., Zeitschel, U., Hoffmann, T. et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathology. Nat Med 14, 1106–1111 (2008). https://doi.org/10.1038/nm.1872
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DOI: https://doi.org/10.1038/nm.1872
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