RT Journal Article SR Electronic T1 Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 12790 OP 12801 DO 10.1523/JNEUROSCI.1794-11.2011 VO 31 IS 36 A1 Anca Alexandru A1 Wolfgang Jagla A1 Sigrid Graubner A1 Andreas Becker A1 Christoph Bäuscher A1 Stephanie Kohlmann A1 Reinhard Sedlmeier A1 Kerstin A. Raber A1 Holger Cynis A1 Raik Rönicke A1 Klaus G. Reymann A1 Elisabeth Petrasch-Parwez A1 Maike Hartlage-Rübsamen A1 Alexander Waniek A1 Steffen Rossner A1 Stephan Schilling A1 Alexander P. Osmand A1 Hans-Ulrich Demuth A1 Stephan von Hörsten YR 2011 UL http://www.jneurosci.org/content/31/36/12790.abstract AB Posttranslational amyloid-β (Aβ) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Aβ species, pyroglutamate-amyloid-β (pE3–Aβ), has been described as a major constituent of Aβ deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated Aβ species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3–Aβ aggregates rapidly and is known to seed additional Aβ aggregation. To directly investigate pE3–Aβ toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human Aβ. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating Aβ and pE3–Aβ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3–Aβ neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3–Aβ formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3–Aβ levels. Hence, lowering the rate of QC-dependent posttranslational pE3–Aβ formation can, in turn, lower the amount of neurotoxic Aβ species in AD.