Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation

• Published in: The Journal of neuroscience Vol. 31; no. 36; pp. 12790 - 12801
• Main Authors: Alexandru, Anca, Jagla, Wolfgang, Graubner, Sigrid, Becker, Andreas, Bäuscher, Christoph, Kohlmann, Stephanie, Sedlmeier, Reinhard, Raber, Kerstin A, Cynis, Holger, Rönicke, Raik, Reymann, Klaus G, Petrasch-Parwez, Elisabeth, Hartlage-Rübsamen, Maike, Waniek, Alexander, Rossner, Steffen, Schilling, Stephan, Osmand, Alexander P, Demuth, Hans-Ulrich, von Hörsten, Stephan
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 07-09-2011
• Subjects: Aging - pathology; Aging - psychology; Alzheimer Disease - pathology; Amyloid beta-Protein Precursor - biosynthesis; Animals; Behavior, Animal; Brain - pathology; Enzyme-Linked Immunosorbent Assay; Gliosis - pathology; Heredodegenerative Disorders, Nervous System - genetics; Heredodegenerative Disorders, Nervous System - pathology; Heredodegenerative Disorders, Nervous System - psychology; Hippocampus - pathology; Humans; Immunohistochemistry; Kinetics; Long-Term Potentiation - physiology; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Microscopy, Electron; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Phenotype; Postural Balance - physiology; Protein Processing, Post-Translational; Pyrrolidonecarboxylic Acid - metabolism; Reflex, Startle - physiology; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1794-11.2011

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.