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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

Authors

  • Alexandru A
  • Jagla W
  • Graubner S
  • Becker A
  • Bäuscher C
  • Kohlmann S
  • Sedlmeier R
  • Raber KA
  • Cynis H
  • Rönicke R
  • Reymann KG
  • Petrasch-Parwez E
  • Hartlage-Rübsamen M
  • Waniek A
  • Rossner S
  • Schilling S
  • Osmand AP
  • Demuth HU
  • von Hörsten S

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

September 7, 2011

Associated Grants

None

Mesh Terms

  • 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