title: Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation.
abstract: 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.
authors: Ingenium Pharmaceuticals, 82152 Martinsried, Germany.
authors: Anca
authors: A
authors: Alexandru
authors: Wolfgang
authors: W
authors: Jagla
authors: Sigrid
authors: S
authors: Graubner
authors: Andreas
authors: A
authors: Becker
authors: Christoph
authors: C
authors: Bäuscher
authors: Stephanie
authors: S
authors: Kohlmann
authors: Reinhard
authors: R
authors: Sedlmeier
authors: Kerstin A
authors: KA
authors: Raber
authors: Holger
authors: H
authors: Cynis
authors: Raik
authors: R
authors: Rönicke
authors: Klaus G
authors: KG
authors: Reymann
authors: Elisabeth
authors: E
authors: Petrasch-Parwez
authors: Maike
authors: M
authors: Hartlage-Rübsamen
authors: Alexander
authors: A
authors: Waniek
authors: Steffen
authors: S
authors: Rossner
authors: Stephan
authors: S
authors: Schilling
authors: Alexander P
authors: AP
authors: Osmand
authors: Hans-Ulrich
authors: HU
authors: Demuth
authors: Stephan
authors: S
authors: von Hörsten
mesh_terms: D000375:Aging / Q000473:pathology / Q000523:psychology; D000544:Alzheimer Disease / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005911:Gliosis / Q000473:pathology; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D004856:Postural Balance / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D013216:Reflex, Startle / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D011761:Pyrrolidonecarboxylic Acid