Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation
Open accessAbstract
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.
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In TBA2.1 mice, Aβ and AβpE3 accumulated mainly in the CA1 layer of the hippocampus, with ~30% neuron loss at 3 months and ~50% less neurons at 5 months, accompanied by robust astrocyte and microglia activation.
“These mice accumulated Aβ and AβpE3 mainly in the CA1 layer of the hippocampus and present with ~30% neuron loss at 3 and ~50% less neurons at 5 months of age in this brain area. This was accompanied by a robust activation of astrocytes and microglia, arguing for an AβpE3-induced cellular neurotoxicity.”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [98]
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Bouter, Y., Dietrich, K., Wittnam, J. L., Rezaei-Ghaleh, N., Pillot, T., Papot-Couturier, S., Lefebvre, T., Sprenger, F., Wirths, O., Zweckstetter, M., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1129-2 · Cited by 175 · see citing works
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- Authors
- Alexandru, A., Jagla, W., Graubner, S., Becker, A., Bäuscher, C., Kohlmann, S., Sedlmeier, R., Raber, K. A., Cynis, H., Rönicke, R., Reymann, K. G., Petrasch-Parwez, E., Hartlage-Rübsamen, M., Waniek, A., Rossner, S., Schilling, S., Osmand, A. P., Demuth, H.-U., & von Hörsten, S.
- Affiliations
- Ingenium (Germany) (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Probiodrug (Germany) (DE)
- German Center for Neurodegenerative Diseases (DE)
- Leipzig University (DE)
- University of Tennessee at Knoxville (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-09-07
- Volume
- 31
- Issue
- 36
- Pages
- 12790-12801
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623394
- OpenAlex
- W2032958786
- Cited by
- 102
- References
- 55
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 2 · 2021: 11 · 2020: 8 · 2019: 6 · 2018: 11 · 2017: 4 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 8 · 2012: 10
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Qucosa (Saxon State and University Library Dresden) (submittedVersion, cc-by-nc-sa)
- DZNE Pub (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- pyroglutamate amyloid-beta, glutaminyl cyclase, Alzheimer's disease, hippocampal neurodegeneration, transgenic mice, amyloid-beta aggregation, neurotoxicity, long-term potentiation, microglial activation, astrocyte activation, post-translational modification
- MeSH terms
- Aging, Alzheimer Disease, Animals, Behavior, Animal, Brain, Enzyme-Linked Immunosorbent Assay, Postural Balance, Gliosis, Hippocampus, Humans, Immunohistochemistry, Kinetics, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Microscopy, Electron, Neuronal Plasticity, Phenotype, Protein Processing, Post-Translational, Pyrrolidonecarboxylic Acid, Reflex, Startle, Amyloid beta-Protein Precursor, Long-Term Potentiation, Reverse Transcriptase Polymerase Chain Reaction, Heredodegenerative Disorders, Nervous System, Mice
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