@article {Alexandru12790, author = {Anca Alexandru and Wolfgang Jagla and Sigrid Graubner and Andreas Becker and Christoph B{\"a}uscher and Stephanie Kohlmann and Reinhard Sedlmeier and Kerstin A. Raber and Holger Cynis and Raik R{\"o}nicke and Klaus G. Reymann and Elisabeth Petrasch-Parwez and Maike Hartlage-R{\"u}bsamen and Alexander Waniek and Steffen Rossner and Stephan Schilling and Alexander P. Osmand and Hans-Ulrich Demuth and Stephan von H{\"o}rsten}, title = {Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate{\textendash}Aβ Formation}, volume = {31}, number = {36}, pages = {12790--12801}, year = {2011}, doi = {10.1523/JNEUROSCI.1794-11.2011}, publisher = {Society for Neuroscience}, abstract = {Posttranslational amyloid-β (Aβ) modification is considered to play an important role in Alzheimer{\textquoteright}s disease (AD) etiology. An N-terminally modified Aβ species, pyroglutamate-amyloid-β (pE3{\textendash}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{\textendash}Aβ aggregates rapidly and is known to seed additional Aβ aggregation. To directly investigate pE3{\textendash}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{\textendash}Aβ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3{\textendash}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{\textendash}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{\textendash}Aβ levels. Hence, lowering the rate of QC-dependent posttranslational pE3{\textendash}Aβ formation can, in turn, lower the amount of neurotoxic Aβ species in AD.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/31/36/12790}, eprint = {https://www.jneurosci.org/content/31/36/12790.full.pdf}, journal = {Journal of Neuroscience} }