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Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model
Open accessAbstract
It is well established that only a fraction of Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.
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“At ~2 months of age, a severe neurological phenotype with growth retardation, loss of motor coordination, and ataxia became evident, together with AβpE accumulation and loss of Purkinje cells [63].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [63]
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Metadata
- Authors
- Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H.-U., & Bayer, T. A.
- Affiliations
- University of Göttingen (DE)
- Probiodrug (Germany) (DE)
- Corresponding author
- Bayer, Thomas A.
- Venue
- Acta Neuropathologica
- Published
- 2009-06-23
- Volume
- 118
- Issue
- 4
- Pages
- 487-496
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC2737116
- OpenAlex
- W2127458156
- Cited by
- 174
- References
- 71
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 18 · 2013: 12 · 2012: 19
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Acta Neuropathologica (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- Alzheimer Forschung Initiative
- European Commission (MEST-CT-2005-020013)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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, Alzheimer's disease, neurodegeneration, Purkinje cell degeneration, neurotoxicity, neurological deficit, amyloid precursor protein, BACE, amyloid fibril formation, cerebellum
- MeSH terms
- Analysis of Variance, Animals, Body Weight, Brain, Brain Diseases, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Mice, Transgenic, Nerve Degeneration, Neurons, Peptide Fragments, Phenotype, Purkinje Cells, Amyloid beta-Peptides, Cell Death, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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