Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation.
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.
Pubmed ID: 21900558 RIS Download
Aging | Alzheimer Disease | Amyloid beta-Protein Precursor | Animals | Behavior, Animal | Brain | Enzyme-Linked Immunosorbent Assay | Gliosis | Heredodegenerative Disorders, Nervous System | Hippocampus | Humans | Immunohistochemistry | Kinetics | Long-Term Potentiation | Mice | Mice, Inbred C57BL | Mice, Inbred DBA | Mice, Transgenic | Microscopy, Electron | Neuronal Plasticity | Phenotype | Postural Balance | Protein Processing, Post-Translational | Pyrrolidonecarboxylic Acid | Reflex, Startle | Reverse Transcriptase Polymerase Chain Reaction