Letter abstract
Nature Medicine 14, 1106 - 1111 (2008)
Published online: 28 September 2008 | doi:10.1038/nm.1872
Glutaminyl cyclase inhibition attenuates pyroglutamate A
and Alzheimer's disease–like pathology
Stephan Schilling1, Ulrike Zeitschel2, Torsten Hoffmann1, Ulrich Heiser1, Mike Francke2, Astrid Kehlen1, Max Holzer2, Birgit Hutter-Paier3, Manuela Prokesch3, Manfred Windisch3, Wolfgang Jagla4, Dagmar Schlenzig1, Christiane Lindner5, Thomas Rudolph5, Gunter Reuter5, Holger Cynis1, Dirk Montag6, Hans-Ulrich Demuth1,4 & Steffen Rossner2
Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified A
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 A. Oral application of a glutaminyl cyclase inhibitor resulted in reduced A3(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 Ax–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 A3(pE)–42 acts as a seed for A aggregation by self-aggregation and co-aggregation with A1–40/42. Therefore, A3(pE)–40/42 peptides seem to represent A forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-A 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.
- Probiodrug AG, Weinbergweg 22, 06120 Halle/S., Germany.
- Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany.
- JSW-CNS Research GmbH, Parkring 12, 8074 Grambach/Graz, Austria.
- Ingenium Pharmaceuticals GmbH, Fraunhoferstrasse 13, 82152 Munich-Martinsried, Germany.
- Institute of Biology, Department of Genetics, University of Halle-Wittenberg, Weinbergweg 10, 06120 Halle/S., Germany.
- Research Group Neurogenetics, Leibniz Institute for Neurobiology, Brenneckestrasse 6, 39118 Magdeburg, Germany.
Correspondence to: Hans-Ulrich Demuth1,4 e-mail: hans-ulrich.demuth@probiodrug.de
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